## Factors That Alter Clearance

Body Surface Area (BSA)

Most literature values for clearance are expressed as volume/kg/time or as volume/70 kg/time. There is some evidence, however, that drug clearance is best adjusted on the basis of BSA rather than weight.

The patient’s BSA can be obtained from a nomogram, estimated from below:

BSA in m2 = [(Patient’s Weight in Kg / 70 kg)^0.7]*(1.73 m2)

or

BSA in m2 = (W^0.425)(H^0.725)*0.007184

The following formulas can be used to adjust the clearance values reported in the literature for specific patients. There are other equations one can use depending on units used in the literature for clearance.

• Patient’s Cl = (Literature Cl per m2)(Patient’s BSA)
• Patient’s Cl = (Literature Cl per 70 kg) (Patient’s BSA / 1.73 m2)
• Patient’s Cl = (Literature Cl per 70 kg)(Patient’s Weight in Kg / 70 kg)
• Patient’s Cl = (Literature Cl per kg)(Patient’s Weight in kg)

When patients do not differ significantly from 70 kg, the difference between using weight versus BSA becomes less significant.

The underlying assumption in using weight or BSA to adjust clearance is that the patient’s liver and kidney size (and hopefully function) vary in proportion to these physical measurements. This may not always be the case; therefore, clearance values derived from the patient populations having a similar age and size should be used whenever possible. If the patient’s weight is reasonably close to 70 kg (BSA = 1.73 m2), the patient’s calculated clearance will be similar whether weight or BSA are used to calculate clearance. If, however, the patient’s weight differs significantly from 70 kg, then the use of weight or surface area is likely to generate substantially different estimates of the patient’s clearance. When a patient’s size is substantially greater or less than the standard 70 kg, or 1.73 m2, a careful assessment t should be made to determine if the patient’s body stature is normal, obese, or emaciated. In obese and emaciated patients, neither weight nor surface area is likely to be helpful in predicting clearance, since the patient’s body size will not reflect the size or function of the liver and kidney.

Plasma Protein Binding

For highly protein-bound drugs, diminished plasma protein binding is associated with a decrease in reported steady-state plasma drug concentrations (total of unbound plus free drug) for any given dose that is administered. It would be misleading, however, to assume that because the calculated clearance is increased, the amount eliminated per unit of time has increased. Actually the amount eliminated per unit of time equals is the production of both Cl and C. In summary, when the same daily dose of a drug is given in the presence of diminished protein binding, an amount equal to that dose will be eliminated from the body each day at steady state despite a diminished steady-state plasma concentration and an increase in the calculated clearance. This is one way to explain the un-changed RE (rate of elimination). In another way to explain, when Css ave changes, the free or unbound fraction of drug in the plasma generally increases (even though Css ave decreases) with diminished plasma protein binding. As a result, the amount of free drug eliminated per unit of time remains unchanged.

And also what is important is that the pharmacologic effect achieved will be similar to that produced by the higher serum concentration observed under normal protein binding conditions. This example re-emphasizes the principle that clearance alone is not a good indicator of the amount of drug eliminated per unit of time (RE).

Extraction Ratio

The direct proportionality between calculated clearance and fraction unbound (fu) does not apply to drugs that are so efficiently metabolized or excreted that some (perhaps all) of the drug bound to plasma protein is removed as it passes through the eliminating organ. In this situation the plasma protein acts as a “transport system” for the drug, carrying it to the eliminating organs, and clearance becomes dependent on the blood or plasma flow to the eliminating organ. To determine whether the clearance for a drug with significant plasma binding will be influenced primarily by blood flow or plasma protein binding, its extraction ratio is estimated and compared to its fu value.

The extraction ratio is the fraction of the drug presented to the eliminating organ that is cleared after a single pass through that organ. It can be estimated by dividing the blood or plasma clearance of a drug by the blood or plasma flow to the elimination organ. At rest, the blood flow to the liver via the portal vein is at a rate of 1300 mL/min, and the other 500 mL/min is suppled by the hepatic artery. If the extraction ratio exceeds the free fraction (fu), then the plasma proteins are acting as a transport system and clearance will not change in proportion to fu. If, however, the extraction ratio is less than fu, clearance is likely to increase by the same proportion that fu changes. This approach does not take into account other factors that may affect clearance such as red blood cell binding, elimination from red blood cells, or changes in metabolic function.

Renal and Hepatic Function

Drugs can be eliminated or cleared as unchanged drug through the kidney (renal clearance) and by metabolism in the liver (metabolic clearance). These two routes of clearance are assumed to be independent of one another and additive.

Clt = Clm + Clr (total Cl = metabolic CI + renal Cl)

Because the kidneys and liver function independently, it is assumed that a change in one does not affect the other. Thus, Clt can be estimated in the presence of renal or hepatic failure or both. Because metabolic function is difficult to quantitate, Clt is most commonly adjusted when there is decreased renal function:

A clearance that has been adjusted for renal function can be used to estimate the maintenance dose for a patient with diminished renal function. This adjusted clearance equation, however, is only valid if the drug’s metabolites are inactive and if the metabolic clearance is indeed unaffected by renal dysfunction as assumed. A decrease in the function of an organ of elimination is most significant when that organ serves as the primary route of drug elimination. However, as the major elimination pathway becomes increasingly compromised, the “minor” pathway becomes more significant because it assumes a greater proportion of the total clearance. For example, a drug that is usually 67% eliminated by the renal route and 33% by the metabolic route will be 100% metabolized in the event of complete renal failure; the total clearance, however, will only be one-third of the normal value.

As an alternative to adjusting Clt to calculate dosing rate, one can substitute fraction of the total clearance that is metabolic and renal for Clm and Clr. Using this technique the equation below can be derived.

The Dosing Rate Adjustment Factor can be used to adjust the maintenance dose for a patient with altered renal function.

Most pharmacokinetic adjustments for drug elimination are based on renal function because hepatic function is usually more difficult to quantitate. Elevated liver enzymes do reflect liver damage but are not a good measure of function. Hepatic function is often evaluated using the prothrombin time (or INR), serum albumin concentration, and serum bilirubin concentration. Unfortunately, each of these laboratory tests is affected by variables other than altered hepatic function. For example, the serum albumin may be low due to decreased protein intake or increased renal or GI loss, as well as decreased hepatic function. Although liver function tests do not provide quantitative data, pharmacokinetic adjustments must still take into consideration liver function because this route of elimination is important for a significant number of drugs.

Cardiac Output

Cardiac output also affects drug metabolism. Hepatic or metabolic clearances for some drugs can be decreased by 25% to 50% in patients with congestive heart failure. For example, the metabolic clearances of theophylline and digoxin are reduced by approximately one-half in patients with congestive heart failure. Since the metabolic clearance for both of these drugs is much lower than the hepatic blood or plasma flow (low extraction ratio), it would not have been predicted that their clearances would have been influenced by cardiac output or hepatic blood flow to this extent. The decreased cardiac output and resultant hepatic congestion must, in some way, decrease the intrinsic metabolic capacity of the liver.

## Creatinine Clearance Estimation – Non-Steady State

Using non-steady-state serum creatinine values to estimate creatinine clearance is difficult, and a number of approaches have been proposed. The author use Equation 1 below to estimate creatinine clearance when steady-state conditions have not been achieved.

ClCr (mL/min) = { (Production of Creatinine in mg/day) – [(SCr 2 – SCr 1)(V Cr) / t]*(10 dL/L)} * [(1000 mL/L) / (1440 min/day)] / [(SCr 2)(10 dL/L)] [Equation 1]

The daily production of creatinine in milligram is calculated by multiplying the daily production value in mg/kg/day from Table 5 by the patient’s weight in kg. The serum creatinine values in Equation 1 are expressed in units of mg/dL; t is the number (or fraction) of days between the first serum creatinine measurement (SCr1) and the second (SCr2). The volume of distribution of creatinine (Vcr) is calculated by multiplying the patient’s weight in kg times 0.65 L/kg. Equation 1 (or 79) is essentially a modification of the mass balance equation (we will discuss it in another thread later).

where the daily production of creatinine in milligram has replaced the infusion rate of the drug and the second serum creatinine value replaced C ave. The second serum creatinine is used primarily because Equation 1 is most commonly applied when creatinine clearance is decreasing (serum creatinine rising), and using the higher of the two serum creatinine values results in a lower, more conservative estimate of renal function. Some have suggested that the iterative search process, as represented by the combination of Equation 28 and 37 (won’t be discussed here; if needed, please contact Tom for detail), be used:

where C2 represents SCr2, and C represents SCr1. (S)(F)(Dose/tau) represents the daily production of creatinine, and t represents the time interval between the first and second serum creatinine concentrations. Cl represents the creatinine clearance with the corresponding elimination rate constant K being Cl/V or the creatinine clearance divided by the creatinine volume of distribution. As discussed previously, the solution would require an iterative search, and the inherent errors in the calculation process probably do not warrant this type of calculation.

Although Equation 1 (or Equation 79) can be used to estimate a patient’s creatinine clearance when a patient’s serum creatinine is rising or falling, there are potential problems associated with this and all other approaches using non-steady-state serum creatinine values. First, a rising  serum creatinine concentration may represent a continually declining renal function. To help compensate for the latter possibility, the second creatinine (SCr2) rather than the average is used in the denominator of Equation 1/79. Furthermore, there are non-renal routes of creatinine elimination that become significant in patients with significantly diminished renal function. Because as much as 30% of a patient’s daily creatinine excretion is the result of dietary intake, the ability to predict a patient’s daily creatinine production in the clinical setting is limited. One should also consider the potential errors in estimating creatinine production for the critical ill patient, the errors in serum creatinine measurements, and the uncertainty in the volume of distribution estimate for creatinine. Estimating creatinine clearance in a patient with a rising or falling serum creatinine should be viewed as a best guess under difficult conditions, and ongoing reassessment of the patient’s renal function is warranted.

## Creatinine Clearance Estimation – Steady State

Different from most drug administration regimens, creatinine is constantly produced and released into plasma by the body muscle mass. Because many drugs are partially or totally eliminated by the kidney, an accurate estimation of renal function is an important component in the application of pharmacokinetics to designing drug therapy regimens. Creatinine clearance as determined by a urine collection and corresponding plasma sample is considered by many clinicians to be the most accurate test of renal function. In the clinical setting, the time delay and the difficulty in obtaining the 24-hour creatinine collection limit the utility of the 24-hour urine collection. In addition, all too often, the urine collection is inaccurate because a portion is accidentally discarded or the time of collection is shorter or longer than requested. Perhaps, the most common error is an incomplete collection, which will result in an underestimation of renal function. Because decisions with regard to drug dosing must often be made quickly, several authors have suggested a variety of methods by which creatinine clearance (ClCr) can be estimated using a serum creatinine value. The most accurate of these equations include serum creatinine, body weight or size, age, and gender.

Creatinine Pharmacokinetics

The pharmacokinetics of creatinine is presented in far more detail elsewhere, but a brief overview is necessary. Creatinine is a metabolic by-product of muscle, and its rate of formation (RA) is primarily determined by an individual’s muscle mass or lean body weight. It varies, therefore, with age (lower in the elderly) and gender (lower in the females). For any given individual, the rate of creatinine production is assumed to be constant. Once creatinine is released from muscle into plasma, it is eliminated almost exclusively by renal glomerular filtration. Any decrease in the glomerular filtration rate ultimately results in a rise in the serum creatinine level until a new steady state is reached and the amount of creatinine cleared per day equals the rate of production. In other words, at steady state, the rate in must equal the rate out. Since the rate of creatinine production remains constant even when renal clearance diminishes, the serum creatinine must rise until the product of the clearance and the serum creatinine again equals the rate of production.

Creatinine, RA = RE

Estimating Creatinine Clearance from Steady-State Serum Creatinine Concentrations

Basic Rationale

The degree to which a steady-state serum creatinine rises is inversely proportional to the decrease in creatinine clearance. Therefore, the new creatinine clearance can be estimated by multiplying a normal ClCr value by the fractional change in the serum creatinine: normal SCr/patient’s SCrss. For the 70-kg man, it can be assumed that the normal SCr is 1.0 mg/dL and that the corresponding ClCr is 120 mL/min.

New ClCr = (120 mL/min) [1 mg/dL / SCr ss] (Equation 1)

On the basis of this concept, one can see that each time the serum creatinine doubles, the creatinine clearance falls by half and that small changes in the serum at low concentrations are of much greater consequence than equal changes in the serum creatinine at high concentrations. To illustrate, if a patient with a normal serum creatinine of 1.0 mg/dL is reported to have a new steady-state serum creatinine of 2 mg/dL, the creatinine clearance has decreased from 120 to 60 mL/min. However, if a patient with chronic renal dysfunction has a usual serum creatinine of 4 mg/dL (ClCr = 30 mL/min), a similar 1.0 mg/dL increase in the serum creatinine to 5 mg/dL would result in a small drop in the ClCr (6 mL/min) and a new clearance value of 24 mL/min. However, at some point even small changes in ClCr can be physiologically significant to the patient. As an example, for a patient with a creatinine clearance of 100 mL/min to have their renal function decline by 10 mL/min is of very little consequence, but for a patient with a creatinine clearance of 15 mL/min, a 10 mL/min decrease would probably change their clinical status from a patient with very poor renal function to a patient who would require dialysis.

The estimation of ClCr from SCr ss alone is reasonably satisfactory as long as the patient’s daily creatinine production is average (i.e., 20 mg/kg/day); the patient weighs approximately 70 kg and the serum creatinine is at steady state (i.e., not rising or falling). These conditions are usually present in the young healthy adult, but young healthy adults are not the typical patients for whom pharmacokinetic manipulations are most useful.

Adjusting to Body Size: Weight or Body Surface Area

To account for any changes in creatinine production and clearance that may result from a difference in body size, Equation 1 can be modified to compensate for any deviation in BSA from the 70-kg patient (1.73 m2):

The patient’s BSA can be obtained from a nomogram, estimated from Equation 2:

BSA in m2 = [(Patient’s Weight in Kg / 70 kg)^0.7]*(1.73 m2)

or calculated from the following equation:

BSA in m2 = (W^0.425)(H^0.725)*0.007184

where BSA is in meters squared (m2), W is weight in kilograms, and H is the patient’s height in centimeters.

A disadvantage of using only weight or BSA is that the elderly or emaciated patients who have a reduced muscle mass do not have a “normal” creatinine clearance of 120 mL/min/1.73 m2 with a serum creatinine value of 1.0 mg/dL. For this reason, it may be erroneous to assume that a SCr of 1.0 mg/dL is indicative of a creatinine clearance of 120 mL/min/1.73 m2 in these individuals.

On average, as patients age, their muscle mass represents a smaller proportion of their total weight and creatinine production is decreased (Table 5). There are a number of equations that consider age, gender, body size, and serum creatinine when calculating or estimating creatinine clearance for adults. Although all these methods are similar and equivalent in clinical practice, the most common method used by clinicians is probably the one proposed by Cockcroft and Gault.

ClCr for males (mL/min) = (140 – Age)(Weight) / [(72)(SCr ss)] [Equation 3]

ClCr for females (mL/min) = (0.85)(140 – Age)(Weight) / [(72)(SCr ss)] [Equation 4]

where age is in years, weight is in kg, and serum creatinine is in mg/dL. Equation 3 and 4 calculate creatinine clearance as mL/min for the patient’s characteristics entered into the equation.

The two most critical factors to consider when using Equation 3 and 4 are the assumptions that the serum creatinine is at steady state and the weight, age, and gender of the individual reflect normal muscle mass. For example, when estimating a creatinine clearance for an obese patient, an estimate of the non-obese or ideal body weight (IBW) should be used in Equation 3 and 4. This estimate can be based on IBW tables or the following equations.

TBW Significantly Larger than IBW

Ideal Body Weight for males in kg = 50 + (2.3)(Height in Inches > 60) [Equation 5]

Ideal Body Weight for female in kg = 45 + (2.3)(Height in Inches > 60) [Equation 6]

It should be pointed out, however, that an IBW derived from a patient’s height, as in Equation 5 and 6, may not represent the actual non-obese weight of a patient. Although there are some potential flaws in estimating the non-obese weight from height, the IBW is usually preferable to using the actual weight [total body weight (TBW)] when a patient is markedly obese. As a clinical guideline, one approach is to make an adjustment for IBW if the patient’s actual weight is > 120% of their IBW.

There are studies indicating that TBW overestimates and IBW underestimates renal function in the morbidly obese patient. It has been suggested that an adjusted body weight between IBW and TBW be used to estimate renal function in obese individuals. While this adjustment factor is variable, 40% of the excess weight is commonly used:

Adjusted Body Weight = IBW + (0.4)(TBW – IBW) [Equation 7]

where IBW is the patient’s ideal body weight in kg as calculated from Equation 5 and 6, and TBW is the patient’s total body weight in kg.

There are other factors not considered in these equations for IBW and Adjusted Body Weight. As an example, in patients with extensive spacing of fluid (i.e., edema or ascites), the liters (kilograms) of excess third-space fluid should probably not be included in the patient’s estimate of TBW. As an example, consider a 5-foot 4-inch male patient weighting 75 kg and having an estimated 15 kg of edema and ascitic fluid. Using the patient’s height (64 inches) and weight (75 kg) might suggest that the patient is more than 120% over his IBW and therefore “clinically obese” for the purposes of doing pharmacokinetic calculations.

For this patient, IBW = 59.2, TBW/IBW = 127%. However, the patient is not obese but rather has a significant amount of interstitial fluid accumulated. This is obvious if we subtract the excessive third-space fluid weight of 15 kg from his total weight of 75 kg, resulting in a weight of 60 kg. Clearly, the difference between the “non-excess third-space fluid weight” of 60 kg and the estimated IBW of 59.2 kg is so small that the patient would not be considered clinically obese.

Likewise, when calculating an Adjusted Body Weight, it would be the patient’s weight minus any significant third-space fluid weight that would be used in Equation 7. The excessive third-space fluid weight may or may not be important to consider in making pharmacokinetic calculations. As an example, significant third-space fluid does contribute to the apparent volume of distribution for some drugs, but is unlikely to be an important contributor to volume of distribution if the apparent volume of distribution is large or if there is significant plasma protein binding.

Third-space fluid weight is unlikely to contribute to and should not be used when initial estimates of clearance are made. However, while not directly influencing clearance, it is possible that the presence of ascites or edema may indicate the presence of a disease process that is known to alter clearance.

TBW Significantly Smaller than IBW

Patients who weigh significantly less than their IBW or are emaciated also require special consideration when estimating renal function. While it may seem counterintuitive, a creatinine clearance calculated for an emaciated subject using the patient’s weight also tends to over predict the patient’s creatinine clearance. This is because patients who are emaciated tend to have a disproportionally greater loss in muscle mass than TBW. Consequently, serum creatinine in the denominator of Equation 3 and 4 decreases more than the weight in the numerator, resulting an overestimate of creatinine clearance. For this reason, if the patient’s actual weight is less than their IBW, the actual weight should be used when calculating creatinine clearance in emaciated subjects. Even then, the creatinine clearance is likely to be overestimated.

Low Serum Creatinine Level

In addition, it has been suggested that when serum creatinine values are < 1.0 mg/dL, more accurate predictions of creatinine clearance can be obtained if these levels are upwardly adjusted or normalized to a value of 1.0 mg/dL. This suggestion is based on the assumption that low serum creatinine values are related to small muscle mass and a decreased creatinine production rather than to an unusually large creatinine clearance. It is a common practice for clinicians to normalize serum creatinine values < 1 to 1 mg/dL. However, there is evidence suggesting that using the actual serum creatinine values of < 1 mg/dL result in more accurate estimates of creatinine clearance. Because of this continuing controversy and the difficulty in estimating creatine clearance accurately, it is important to use clinical judgement in evaluation the risk versus the benefit of drug therapy. When a serum creatinine of < 1mg/dL is used in Equation 3 and 4, most clinicians would recommend setting an upper limit for creatinine clearance. As an example, a 50-year-old man weighing 60 kg with a serum creatinine of 0.5 mg/dL would have a calculated creatinine clearance of 150 mL/min if the serum creatinine of 0.5 mg/dL is used. And a value of 75 mL/min if the serum creatinine is normalized to 1 mg/dL.

Even if the first method is used, many clinicians would suggest that an upper limit for a calculated creatinine clearance should be set at somewhere near 120 mL/min. Of course in specific situations (e.g., very large, non-obese, young healthy male patient), a creatinine clearance of more than 120 mL/min might be appropriate to consider. Therefore, whether to normalize a patient’s serum creatinine and whether there should be some upper limit for the calculated value of creatinine clearance should be dictated by clinical judgement rather than a specific rule.

Estimating Time to Reach a Steady-State Serum Creatinine Level

All the above methods for estimating ClCr require a steady-state serum creatinine concentration. When a patient’s renal function suddenly changes, some period of time will be required to achieve a new steady-state serum creatinine concentration. In this situation, it is important to be able to estimate how long it will take for the SCr to reach steady state. If a rising serum creatinine is used in any of the previous equations, the patient’s creatinine clearance will be overestimated.

As presented earlier, half-life is a function of both the volume of distribution and clearance. If the volume of distribution of creatinine (0.5 to 0.7 L/kg) is assumed to remain constant, the time required to reach 90% of steady state in patient with normal renal function is less than 1 day. As an example, the average 70-kg patient with a creatinine clearance of 120 mL/min (7.2 L/hr) with a volume of distribution for creatinine of 45.5 L (0.65 L/kg) would be expected to have a creatinine t1/2 of 4.4 hours.

Under these conditions, 90% of steady state should be achieved in approximately 15 hours (3.3 t1/2s). However, if the same patient had a creatinine clearance of 10 mL/min (0.6 L/min), the creatinine t1/2 would be 52.5 hours and more than a week would be required to ensure that steady state had been achieved. One useful approach, that helps clinicians to make relatively rapid assessments of SCr, is to remember that as a drug (in this case creatinine) concentration is accumulating toward steady state, half of the total change will occur in the first half-life. Therefore, two serum creatinine concentrations obtained several hours apart (8 to 12 hours) that appear to be similar (i.e., not increasing or declining significantly) and that represent reasonably normal renal function probably represent steady-state conditions. As renal function declines, proportionately longer intervals between creatinine measurements are required to assure that steady-state conditions exits.

In clinical practice, patients occasionally have a slowly increasing serum creatinine. As an example, a patient might have the following serum creatinine concentrations on 4 consecutive days: 1, 1.2, 1.6, and 1.8 mg/dL. First, it should be recognized that the increase in serum creatinine from day 1 to day 2 could be due to assay error alone, as the absolute error for most creatinine assays is +- 0.1 to 0.2 mg/dL. Also, given that the t1/2 of creatinine at concentrations in the range of 1 to 2 mg/dL is approximately 4 to 8 hours, steady state should have been achieved in the first day. Therefore, the continued increase in serum creatinine probably reflects ongoing changes in creatinine clearance over the 4 days. The difficult clinical issue is not what the creatinine clearance is on each of the 4 days, but rather what it will be tomorrow, what is the cause, and how to prevent or minimize the ongoing renal damage.

## [Clinical Art][Pharmacokinetics] Interpretation of Plasma Drug Concentrations (Steady-State)

Plasma drug concentration are measured in the clinical setting to determine whether a potentially therapeutic or toxic concentration has been produced by a given dosage regimen. This process is based on the assumption that plasma drug concentrations reflect drug concentrations at the receptor and, therefore, can be correlated with pharmacologic response. This assumption is not always valid. When plasma samples are obtained at inappropriate times or when other factors (such as delayed absorption or altered plasma binding) confound the usual pharmacokinetic behavior of a drug, the interpretation of serum drug concentrations can lead to erroneous pharmacokinetic and pharmacodynamic conclusions and utimately inappropriate patient care decisions. These facors are discussed below.

Confounding Factors

To properly interpret a plasma concentration, it is essential to know when a plasma sample was obtained in relation to the last dose administered and when the drug regimen was initiated.

• If a plasma sample is obtained before distribution of the drug into tissue is complete, the plasma concentration will be higher than predicted on the basis of dose and response. (avoidance of distribution)
• Peak plasma levels are helpful in evaluating the dose of antibiotics used to treat severe, life-threatening infections. Although serum concentrations for many drugs peak 1 to 2 hours after an oral dose is administered, factors such as slow or delayed absorption can significantly delay the time at which peak serum concentrations are attained. Large errors in the estimation of Css max can occur if the plasma sample is obtained at the wrong time. Therefore, with few exceptions, plasma samples should be drawn as trough or just before the next dose (Css min) when determining routine drug concentration in plasma. These trough levels are less likely to be influenced by absorption and distribution problems. (slow or delayed absorption)
• When the full therapeutic response of a given drug dosage regimen is to be assessed, plasma samples should not be obtained until steady-state concentrations of the drug have been achieved. If drug doses are increased or decreased on the basis of drug concentrations that have been measured while the drug is still accumulating, disastrous consequences can occur. Nevertheless, in some clinical situations it is appropriate to measure drug levels before steady state has been achieved. If possible, plasma samples should be drawn after a minimum of two half-lives beause clearance values calculated from drug levels obtained less than one half-life after a regimen has been initiated are very sensitive to small differences in the volume of distribution and minor assay errors. (Whether steady-state attained)
• The impact of drug plasma protein binding on the interpretation of plasma drug coencentration has been discussed in thread "The Plasma Protein Concentration and The Interpretation of TDM Report" before.

Revising Pharmacokinetic Parameters

The process of using a patient's plasma drug concentration and dosing history to determine patient-specific pharmacokinetic parameters can be complex and difficult. A single plasma sample obtained at the appropriate time can yield information to revise only one parameter, either the volume of distribution or clearance, but not both. Drug concentrations measured from poorly timed samples may prove to be useless in estimating a patient's V or Cl values. Thus, the goal is to obtain plasma samples at times that are likely to yield data that can be used with confidence to estimate pharmacokinetic parameters. In addition, it is important to evaluate available plasma concentration data to determine whether they can be used to estiamte, with some degree of confidence, V and/or Cl. The goal in pharmacokinetic revisions is not only to recognize which pharmacokinetic parameter can be revised, but also the accuracy or confidence one has in the revised or patient-specific pharmacokinetic parameter. In the clinical setting, based on the way drugs are dosed and the recommended time to sample, bioavailability is almost never revised, volume of distribution is sometimes revised, and most often clearance is the pharmacokientic parameter that can be revised to determine a patient-specific value.

Volume of Distribution

A plasma concentration that has been obtained soon after administration of an initial bolus is primarily determined by the dose administered and the volume of distribution. This assumes that both the absorption and distribution phases have been avoided.

C1 = (S) (F) (Loading Dose) x e(-kt1) / V (IV Bolus Model)

When e(-kt1) approches 1 (i.e., when t1 is much less than t1/2), the plasma concentration (C1) is primarily a function of the administered dose and the apparent volume of distribution. At this point, very little drug has been eliminated from the body. As a clinical guideline, a patient's volume of distribution can usually be estimated if the absorption and distribution phase are avoided and t1, or the interval between the administration and sampling time, is less than or equal to one-third of the drug's half-life. As t1 exceeds one-third of a half-life, the measured concentration is increasingly infuenced by clearance. As more of the drug is eliminated (i.e., t1 increases), it is difficult to estimate the patient's V with any certainty. The specific application of this clinical guideline depends on the confidence with which one knows clearance. If clearance is extremely variable and uncertain, a time interval of less than one-third of a half-life would be necessary in order to revise volume of distribution. On the other hand, if a patient-specific value for clearance has already been determined, then t1 could exceed one-third of a half-life and a reasonably accurate estimate of volume of distribution could be obtained. It is important to recognize that the pharmacokinetic parameter that most influences the drug concentration is not determined by the model chosen to represent the drug level. For example, even if the dose is modeled as a short infusion, the volume of distribution can still be the important parameter controlling the plasma concentration. V is not clearly defined in the equation (see it below); nevertheless, it is incorporated into the elimination rate constant (K).

C2 =[(S) (F) (Dose/tin) / Cl]*(1-e-ktin)(e-kt2)

Although one would not usually select this equation to demonstrate that the drug concentration is primarily a function of volume of distribution, it is important to recognize that the relationship between the observed drug concentration and volume is not altered as long as the total elapsed time (tin + t2) does not exceed one-third of a half-life.

Our assumption in evaluating the volume of distribution is that although we have not sampled beyond one-third of a t1/2, we have waited until the drug absorption and distribution process is complete.

Clearance

A plasma drug concentration that has been obtained at steady state from a patient who is receiving a constant drug infusion is determined by clearance.

Css ave = (S) (F) (Dose / tau) / Cl

So, the average steady-state plasma concentration is not influenced by volume of distribution. Therefore, plasma concentrations that represent the average steady-state level can be used to estimate a patient's clearnace value, but they cannot be used to estimate a patient's volume of distribution. Generally, all steady-state plasma concentrations within a dosing interval that is short relative to a drug's half-life (tau =<1/3 t1/2) approximate the average concentration. Therefore, these concentrations are also primarily a function of clearance and only minimally influenced by V.

Also the below equation could be used,

Css 1 =[(S)(F)(Dose)/V]/(1-e-kτ)*(e-kt1)

the expected volume of distribution should be retained and the elimination rate constant adjusted such that Css1 at t1 equals the observed drug plasma concentration.

Sensitivity Analysis

Whether a measured drug concentration is a function of clearance or volume of distribution is not always apparent. When this is difficult to ascertain, one can examine the sensitivity or responsiveness of the predicted plasma concentration to a parameter by changing one parameter while holding the other constant. For example, for maintenance infusion, a plasma concentration (C1) at some time intervnal (t1) after a maintenance infusion has been started should be:

C1=[(S)(F)(Dose/τ)/Cl]*(1-e-kt1)

when the fraction of steady that has been reached (1-e-kt1) is small, large changes in clerance are frequently required to adjust a predicted plasma concentration to the appropriate value. If a large percentage change in the clearance value results in a disproportionately small change in the predicted drug level, then something other than clearance is controlling (responsible for) the drug concentration. In this case, the volume of distribution and the amount of drug administered are the primary determinants of the observed concentration. Also in cases where the drug concentration is very low, it might be assay error or sensitivity that is the predominant factor in determining the drug concentration making the ability to revise for any pharmacokinetic parameter limited if not impossible.

This type of sensitivity analysis is useful to reinforce the concept that the most reliable revisions in pharmacokinetic parameters are made when the predicted drug concentration changes by approximately the same percentage as the pharmacokinetic parameter undergoing revision.

When a predicted drug concentration changes in direct proportion, or inverse proportion to an alteration in only one of the pharmacokinetic parameters, it is likely that a measured drug concentration can be used to estimate that patient-specific parameter. But when both clearance and volume of distribution have a significant influence on th prediction of a measured drug concentration, revision of a patient's pharmacokinetic parameters will be less certain because there is an infinite number of combinations for clearance and volume of distribution values that could be used to predict the observed drug concentration. When this occurs, the patient's specific pharmacokinetic characteristics can be estimated by adjusting one or both of the pharmacokinetic parameters. Nevertheless, in most cases additional plasma level sampling will be needed to accurately predict the patient's clearance or volume of distribution so that subsequent dosing regimens can be adjusted.

When the dosing interval is much shorter than the drug's half-life, the changes in concentration within a dosing interval are relatively small, and any drug concentration obtained within a dosing interval can be used as an approximation of the average steady-state concentration. Even though Css max and Css min exist,

Css max =[(S)(F)(Dose)/V]/(1-e-kτ)

and

Css min =[(S)(F)(Dose)/V]/(1-e-kτ)*(e-kτ)

and could be used to predict peak and trough concentrations, a reasonable approximation could also be achieved by using the Css ave, that is

Css ave =(S)(F)(Dose/τ)/Cl

This suggests that even though Css max and Css min do not contain the parameter clearance per se, the elimination rate constant functions in such a way that the clearance derived from Css max or Css min and Css ave would all essentially be the same.

In the situation in which the dosing interval is greater than one-third of a half-life, the use of Css max and Css min are appropriate as not all drug concentrations within the dosing interval can be considered as the Css ave. However, as long as the dosing interval has not been extended beyond one half-life, clearance is still the primary pharmacokinetic parameter that is responsible for the drug concentrations within the dosing interval. Although the elimination rate constant and volume of distribution might be manipulated in Css max and Css min, it is only the product of those two numbers (i.e., clearance) that can be known with any certainty: Cl = (K) (V).

If a drug is administered at a dosing interval that is much longer than the apparent half-life, peak concentrations may be primarily a function of volume of distribution. Since most of the dose is eliminated within a dosing interval, each dose can be thought as something approaching a new loading dose. Of course for steady-state conditions, at some point within the dosing interval, the plasma concentration (Css ave) will be determined by clearance. Trough plasma concentrations in this situation are a function of both clearance and volume of distribution. Since clearance and volume of distribution are critical to the prediction of peak and trough concentrations when the dosing interval is much longer than the drug t1/2, a minimum of two plasma concentrations is needed to accurately establish patient-specific pharmacokinetic parameters and a dosing regimen that will achieve desired peak and trough concentrations.

Choosing A Model to Revise or Estimate A Patient's Clearance at Steady State

As previously discussed, a drug's half-life often determines the pharmacokinetic equation that should be used to make a revised or patient-specific estimate of a pharmacokinetic parameter. A common problem encountered clinically, however, is that the half-life observed in the patient often differs from the expected value. Since a change in either clearance or volume of distribution or both may account for this unexpected value, the pharmacokinetic model is often unclear. One way to approach this dilemma is to first calculate the expected change in plasma drug concentration assocaited with each dose:

delta C = (S) (F) (Dose) / V

where delta C is the change in concentration following the administration of each dose into the patient's volume of distribution. This change in concentration can then be compared to the steady-state trough concentration measured in the patient.

(S) (F) (Dose) / V versus Css min

or

delta C versus Css min

When the dosing interval (tau) is much less than the drug half-life, delta C will be small when compared to Css min. As the dosing interval increases relative to tau, delta C will increase relative to Css min. Therefore, a comparison of delta C or (S) (F) (Dose) / V to Css min can serve as a guide to estimating the drug t1/2 and the most appropriate pharmacokineitc model or technique to use for revision. With few exceptions, drugs that have plasma level monitoring are most often dosed at intervals less than or equal to their half-lives. Therefore, clearance is the pharmacokinetic parameter most often revised or calculated for the patient in question. The following guidelines can be used to select the pharmacokinetic model that is the least complex and therefore the most appropriate to estimate a patient-specific pharmacokientic parameter.

Condition 1

When, (S) (F) (Dose) / V =< 1/4 Css min

Then, tau =<1/3 t1/2

Under these conditions, Css min ≈ Css ave

And Cl can be estimated by Cl = (S) (F) (Dose / tau) / Css ave

Rules/Conditions: Must be at steady state.

Condition 2

When, (S) (F) (Dose) / V =< Css min

Then, tau =< t1/2

Under these conditions, Css min + (1/2) (S) (F) (Dose) / V ≈ Css ave

And Cl can be estimated by Cl = (S) (F) (Dose / tau) / Css ave

Rules/Conditions: Must be at steady state; C is Css min; Bolus model for absorption is acceptable (dosage form is not sustained release; short infusion model is not required, that is, tin =<1/6t1/2)

Conditon 3

When, (S) (F) (Dose) / V > Css min

Then, tau > t1/2

Under these conditions: Css min + (S) (F) (Dose) / V = Css max

where V is an assumed value from the literature.

K is revised (Krevised):

Krevised = ln {[(Css min + (S) (F) (Dose / V)] / Css min} / tau = ln (Css max / Css min) / tau

Rules/Conditions: Must be at steady state; C is Css min; Bolus model for absorption is acceptable (dosage form is not sustained release; short infusion model is not required, that is, tin =< 1/6 t1/2)

Note that the approaches used become more complex as the dosing interval increases relative to the drug half-life. If a drug is administered at a dosing interval less than or equal to one-third of its half-life and the technique in Condition 3 is used to revise clearance, the revised clearance would be correct. The calculation is not wrong, just unnecessarily complex. However, if a drug is administered at a dosing interval that exceeds one half-life and the technique in Condition 1 is used to revise clearance, the revised clearance value would be inaccurate because Css min cannot be assumed to be approximately equal to Css ave. While it could be argued that the technique used in Condition 3 would suffice for all the previous conditions, it is more cumbersome and tends to focus on the intermediate parameters, K and V rather than Cl. One should also be ware that as the dosing interval increases, relative to the drug's half-life, the confidence in a revised clearance diminishes because the volume of distribution, which is an assumed value from the literature, begins to influence the revised clearance to a greater degree. As a general rule, the confidence in Cl is usually good when the dosing interval is < t1/2, steady state has been achieved, and drug concentrations are obtained properly.

## [Endocrinology] The Regulation and Clinical Art of Thyroid Hormones

Thyroid Hormone Synthesis Process

The Source Components of Thyroid Hormone

Thyroglobulin (Tg), plays an important role in the synthesis and storage of thyroid hormone. Tg is a glycoprotein containing multiple tyrosine residues. It is synthesized in the thyroid follicular epithelial cells and secreted through the apical membrane into the follicular lumen, where it is stored in the colloid. A small amount of noniodinated Tg is also secreted through the basolateral membrane into the circulation. Although circulating levels of Tg can be detected under normal conditions, levels are elevated in diseases such as thyroiditis and Graves disease.

Tg can be considered a scaffold upon which thyroid hormone synthesis takes place. Once Tg is secreted into the follicular lumen, it undergoes major posttranslational modification during the production of thyroid hormones. At the apical surface of the thyroid follicular epithelial cells, multiple tyrosine residues of Tg are iodinated, followed by coupling of some of the iodotyrosine residues to form T3 and T4.

The iodide required for thyroid hormone synthesis is readily absorbed from dietary sources, primarily from iodized salt, but also from seafood and plants grown in soil that is rich in iodine. Following its absorption, iodide is confined to the extracellular fluid, from which it is removed primarily by the thyroid (20%) and the kidney (80%). The total excretion of iodide by the kidneys is approximately equal to daily intake. The balance between dietary intake and renal excretion preserves the total extracellular pool of iodide.

The Uptake and Iodination of Iodine

Iodine uptake

Iodide is concentrated in thyroid epithelial cells by an active, saturable, energy-dependent process mediated by a Na+/I symporter located in the basolateral plasma membrane of the follicular cell. Additional tissues that express the Na+/I symporter include the salivary glands, the gastric mucosa, the placenta, and the mammary glands. However, transport of iodine in these tissues is not under TSH regulation.

Iodine efflux (after the transformation from anion cation?, see below)

The iodination of Tg residues is a process that occurs at the apical membrane. Thus, once inside the cell, iodine must leave the follicular cell through apical efflux by an iodide-permeating mechanism consisting of a chloride-iodide transporting protein (iodide channel) located in the apical membrane of the thyroid follicular cell. The uptake, concentration, and efflux of iodide through the iodide channel are all a function of TSH-stimulated transepithelial transport of iodide.

Organification and coupling

In the follicular lumen, tyrosine residues of Tg are iodinated by iodine (I+; formed by oxidation of I by TPO). This reaction requires hydrogen peroxide, which is generated by a flavoprotein Ca++-dependent reduced nicotinamide adenine dinucleotide phosphate oxidase at the apical cell surface and serves as an electron acceptor in the reaction process. Iodine bonds to carbon 3 or to carbon 5 of the tyrosine residues on Tg in a process referred to as the organification of iodine. This iodination of specific tyrosines located on Tg yields monoiodinated tyrosine (MIT) and diiodinated tyrosine (DIT) residues that are enzymatically coupled to form triiodothyronine (T3) or tetraiodothyronine (T4). The coupling of iodinated tyrosine residues, either of 2 DIT residues or of 1 MIT and 1 DIT residues, is catalyzed by the enzyme thyroid peroxidase. Because not all of the iodinated tyrosine residues undergo coupling, Tg stored in the follicular lumen contains MIT and DIT residues as well as formed T3 and T4.

Release of Thyroid Hormone

The synthesis of thyroid hormone takes place in the colloid space. As mentioned previously, the apical surface of the follicular epithelial cell faces the colloid and not the interstitial space, and thus has no access to the bloodstream. Therefore, thyroid hormone release involves endocytosis of vesicles containing Tg from the apical surface of the follicular cell. The vesicles fuse with follicular epithelial phagolysosomes, leading to proteolytic digestion and cleavage of Tg. In addition to the thyroid hormones T4 and T3, the products of this reaction include iodinated tyrosine residues (MIT and DIT). MIT and DIT are deiodinated intracellularly, and iodide is transported by apical efflux into the follicular colloid space, where it is reused in thyroid hormone synthesis. T4 and T3 are released from the basolateral membrane into the circulation. The thyroid gland releases greater amounts of T4 than T3, so plasma concentrations of T4 are 40-fold higher than those of T3 (90 vs 2 nM). Most of the circulating T3 is formed peripherally by deiodination of T4, a process that involves the removal of iodine from carbon 5 on the outer ring of T4. Thus, T4 acts as a prohormone for T3. Although this deiodination occurs predominantly in the liver, some occurs in the thyroid follicular epithelial cell itself. This intrathyroidal deiodination of T4 is the result of TSH stimulation of the type I deiodinase.

Two additional facts regarding thyroid hormone activity and storage should be noted. First, at physiologic levels, T4, is relatively inactive because it possesses 100-fold lower affinity than T3 for binding to the thyroid receptor and does not enter the cell nucleus at high enough concentrations to occupy the ligand-binding site of the thyroid hormone receptor. Second, in contrast to most endocrine glands, which do not have storage capacity for their product, the thyroid gland is able to store 2-3 months' supply of thyroid hormones in the Tg pool.

Transport and Tissue Delivery of Thyroid Hormones

Once thyroid hormones are released into the circulation, most of them circulate bound to protein. Approximately 70% of T4 and T3 is bound to thyroid-binding globulin. Other protein involved in thyroid binding include transthyretin, which binds 10% of T4, and albumin, which binds 15% of T4 and 25% of T3. A small fraction of each hormone (0.03% of T4 and 0.3% of T3) circulates in its free form. This fraction of the circulating hormone pool is bioavailable and can enter the cell to bind to the thyroid receptor. Of the 2 thyroid hormones, T4 binds more tightly to binding proteins than T3 and thus has a lower metabolic clearance rate and a longer half-life (7 days) than T3 (1 day). The kidneys readily excrete free T4 and T3. Binding of thyroid hormones to plasma proteins ensures a circulating reserve and delays their clearance.

The release of hormone from its protein-bound form is in a dynamic equilibrium. Although the role of binding proteins in delivery of hormone to specific tissues remains to be fully understood, it is known that drugs such as salicylate may affect thyroid hormone binding to plasma proteins. The binding-hormone capacity of the individual can also be altered by disease or hormonal changes. The changes in total amount of plasma proteins available to bind thyroid hormone will impact the total amout of circulating thyroid hormone because of a constant homeostatic adjustment to changes in free hormone levels. A decrease in free thyroid hormone because of an increase in plasma-binding proteins will stimulate the release of TSH from the anterior pituitary, which will in turn stimulate the synthesis and release of thyroid hormone from the thyroid gland. In contrast, a decrease in binding-protein levels, with a resulting rise in free thyroid hormone levels, will suppress TSH release and decrease thyroid hormone synthesis and release. These dynamic changes occur throughout the life of the individual, whether in health or disease. Disruption in these feedback mechanisms will result in manifestations of excess or deficient thyroid hormone function.

Thyroid Hormone Metabolism

As already mentioned, the thyroid releases mostly T4 and very small amounts of T3, yet T3 has greater thyroid activity than T4. The main source of circulating T3 is peripheral deiodination of T4 by deiodinases (I, II and III). Approximately 80% of T4 produced by the thyroid undergoes deiodination in the periphery. Approximately 40% of T4 is deiodinated at carbon 5 in the outer ring to yield the more active T3, principally in liver and kidney. In approximately 33% of T4, iodine is removed from carbon 5 in the inner ring to yield reverse T3 (rT3). Reverse T3 has little or no biologic activity, has a higher metabolic clearance rate than T3, and has a lower serum concentration than T3. Following conversion of T4 to T3 or rT3, these are converted to T2,  a biologically inactive hormone. Therefore, thyroid hormone peripheral metabolism is a sequential deiodination process, leading first to a more active form of thyroid hormone (T3) and finally to complete inactivation of the hormone. Thus, loss of a single iodine from the outer ring of T4 produces the active hormone T3, which may either exit the cell, enter the nucleus directly, or possibly even both. Thyroid hormones can be excreted following hepatic sulfo- and glucuronide conjugation and biliary excretion.

Type I deiodinase catalyzes outer- and inner-ring deiodination of T4 and rT3. It is found predominantly in the liver, kidney, and thyroid. It is considered the primary deiodinase responsible for T4 to T3 conversion in hyperthyroid patients in the periphery. This enzyme also converts T3 to T2. The activity of type I deiodinase expressed in the thyroid gland is increased by TSH-stimulated cAMP production and has a significant influence on the amount of T3 released by the thyroid. Propylthiouracil and iodinated x-ray contrast agents such as iopanoic acid inhibit the activity of this enzyme and consequently the thyroidal production of T3.

Type II deiodinase is expressed in the brain, pituitary gland, brown adipose tissue, thyroid, placenta, and skeletal and cardiac muscle. Type II deiodinase has only outer-ring activity and converts T4 to T3. This enzyme is thought to be the major source of T3 in the euthyroid state. This enzyme plays an important role in tissues that produce a relatively high proportion of the receptor-bound T3 themseleves, rather than deriving T3 from plasma. In these tissues, type II deiodinases are an important source of intracellular T3 and provide more than 50% of the nuclear receptor-bound T3. The critical role of type II deiodinases is underscored by the fact that T3 formed in the anterior pituitary is necessary for negative feedback inhibition (long loop) of TSH secretion.

Type III Deiodinase is expressed in the brain, placenta, and skin. Type III deiodinase has inner-ring activity and converts T4 to rT3, and T3 to T2, thus inactivating T4 and T3. This process is an important feature in placental protection of the fetus. The placental conversion of T4 to rT3, and of T3 to T2 reduces the flow of T3 from mother to fetus. Small amounts of maternal T4 are transferred to the fetus and converted to T3, which increases the T3 concentration in the fetal brain, preventing hypothyroidism. In the adult brain, the expression of type III deiodinases is enhanced by thyroid hormone excess, serving as a protective mechanism against high thyroid hormone concentrations.

The Hypothalamic-pituitary-thyroid Axis

Hypothalamic Regulation of Thyroid-Stimulating Hormone Release (releasing factor)

Thyroid hormone synthesis and release are under negative feedback regualtion by the hypothalamic-pituitary-thyroid axis. TRH is a tripeptide synthesized in the hypothalamus and released from nerve terminals in the median eminence from where it is transported through the portal capillary plexus to the anterior pituitary. TRH binds to cell membrane Gq/11 receptors on thyrotrophs of the anterior pituitary gland, where it activates phospholipase C, resulting in the hydrolysis of phosphatidylinositol bisphosphate and the generation of inositol triphosphate and diacylylycerol. This process leads to an increase in the intracellular Ca2+ concentration, resulting in stimulation of exocytosis and release of TSH into the systemic circulation.

Thyroid-Stimulating Hormone Regulation of Thyroid Hormone Release (tropic effect)

TSH is transported in the bloodstream to the thyroid gland, where it binds to the TSH receptor located on the basolateral membrane of thyroid follicular epithelial cells. The TSH receptor is a cell membrane G protein-coupled receptor. Binding of TSH to its receptor initiates signaling through cyclic 3', 5'-adenosine monophosphate (cAMP), phospholipase C, and the protein kinase A signal transduction systems. Activation of adenylate cyclase, formation of cAMP, and activation of protein kinase A regulate iodide uptake and transcription of Tg, thyroid peroxidase (TPO), and the activity of the sodium-iodide (Na+/I) symporter. Signaling through phospholipase C and intracellular Ca2+ regulate iodide efflux, H2O2 production, and Tg iodination. The TSH receptor is an important antigenic site involved in thyroid autoimmune disease. Autoantibodies to the receptor may act as agonists mimicking the actions of TSH, or antagonists in the case of autoimmune hypothyroidism.

TSH receptor activation results in stimulation of all of the steps involved in thyroid hormone synthesis, including 1) iodine uptake and organification, 2) production and release of iodothyronines from the gland, and 3) promotion of thyroid growth. Specifically, the biologic effects of TSH include stimulation of gene transcription of the following: 1) Na+/I symporter, the protein involved in transporting and concentrating iodide in the thyroid epithelial cell; 2) Tg, the glycoprotein that serves as a scaffold for tyrosine iodination and thyroid hormone synthesis, as well as storage of thyroid hormone; 3) TPO, the enzyme involved in catalyzing the oxidation of iodide and its incorporation into thyrosine residues of Tg; and 4) thyroid hormones T4 and T3 (triiodothyronine).

TSH control the energy-dependent uptake and concentration of iodide by the thyroid gland and its transcellular transport through the follicular epithelial cell. However, iodine metabolism within the thyroid can also be reglated independently of TSH. This mechanism is important when plasma iodide levels are elevated (15-20-fold above normal) because this elevation inhibits the organic binding of iodine within the thyroid. This autoregulatory phenomenon consisting of inhibition of the organification of iodine by elevated circulating levels of iodide is known as the Wolff-Chaikoff effect. This effect lasts for a few days and is followed by the so-called escape phenomenon, at which point the organification of intra-thyroidal iodine resumes and the normal synthesis of T4 and T3 returns. The escape phenomenon results from a decrease in the inorganic iodine concentration inside the thyroid gland from downregulation of the Na+/I symporter. This relative decrease in intrathyroidal inorganic iodine allows the TPO-H2O2 system to resume normal activity. The mechanisms responsible for the acute Wolff-Chaikoff effect have not been elucidated but may be caused by the formation of organic iodocompounds within the thyroid.

Thyroid Hormone Regulation of Thyroid-Stimulating Hormone Release (long loop)

The production and release of thyroid hormones are under negative feedback regulation by the hypothalamic-pituitary-thyroid axis. The release of TSH is inhibited mainly by T3, produced by conversion of T4 to T3 in the hypothalamus, and in the anterior pituitary by type II deiodinase. The contribution of this intracellularly derived T3 in producing the negative feedback inhibition of TSH release is greater than that of T3 derived from the circualtion. Other neuroendocrine mediators that inhibit TSH release include dopamine, somatostatin, and glucocorticoids at high levels, which produce partial suppression of TSH release.