Month: March 2016

Drug Biotransformation Pathways

March 30, 2016 Medicinal Chemistry, Pharmacokinetics No comments , , , , ,

Pathway 1/Phase 1 Reactions

Oxidation is probably the most common reaction in xenobiotic metabolism. This reaction is catalyzed by a group of membrane-bound monooxygenases found in the smooth ER of the liver and other extrahepatic tissues, termed the "cytochrome P450 monooxygenase enzyme system". Additionally, P450 has been called a mixed-function oxidase or microsomal hydroxylase. P450 functions as a multicomponent electron-transport system, responsible for the oxidative metabolism of a variety of endogenous substrates and exogenous substances, including drugs, carcinogens, insecticides, plant toxins, environmental pollutants, and other foreign chemicals.

Central to the functioning of this unique superfamily of heme proteins is an iron protoporphyrin. The iron protoporphyrin is coordinated to the sulfur of cysteine and has the ability to form a complex with carbon monoxide, resulting in a complex that has its primary absorption maximum at 450 nm. The most important function of P450 is to "activate" molecular oxygen (dioxygen), permitting the incorporation of one atom of oxygen into an organic substrate molecule concomitant with the reduction of the other atom of oxygen to water. The introduction of a hydroxyl group into the hydrophobic substrate molecule provides a site for subsequent conjugation with hydrophilic compounds (phase 2), thereby increasing the aqueous solubility of the product for transport and excretion from the organism. This enzyme system not only catalyzes xenobiotic transformations in ways that typically lead to detoxication but also, in some cases, in ways that lead to products having  greater cytoxic, mutagenic, or carcinogenic properties.

Drug Conjugation Pathways (Phase 2)

Conjugation reactions represent probably the most important xenobiotic biotransformation reation. Xenobiotics are as a rule lipophilic, well absorbed from the blood, but excreted slowly in the urine. Only after conjugation (Phase 2) reactions have added an ionic hydrophilic moiety, such as glucuronic acid, sulfate ester, or glycine, to the xenobiotic is water solubility increased and lipid solubility decreased enough to make urinary eliminiation possible. The major proportion of the administered drug dose is excreted as conjugates into the urine and bile. Conjugation reactions can be preceded by Phase 1 reactions. For xenobiotics with a functional group available for conjugation, conjugation can be its fate.

The major conjugation reactions were traditionally thought to terminate pharmacologic activity by transforming the parent drug or Phase 1 metabolites into readily excreted ionic polar products. Moreover, these terminal metabolites would have no significant pharmacologic activity. This long-established view has changed with the discoveries that morphine 6-glucuronide has more analgesic activity than morphine in humans and that minoxidil sulfate is the active metabolite for the antihypertensive minoxidil. For most xenobiotics, conjugation is a detoxification mechanism. However, some compounds could form reactive intermediates that have been implicated in carcinogenesis, allergic reactions, and tissue damage.

Factors Affecting Metabolism

March 30, 2016 Medicinal Chemistry No comments , , , , , , , ,

Drug therapy is becoming oriented more toward controlling metabolic, genetic, and environmental illnesss rather than short-term therapy associated with infectious disease. In most cases, drug therapy lasts for months or even years, and the problems of drug-drug interactions and chronic toxicity from long-term drug therapy have become more serious. Therefore, a greater knowledge of drug metabolism is essential. Several factors influencing xenobiotic metabolism include:

1.Genetic factors. Individual differences in drug effectiveness (drug sensitivity or drug resistance), drug-drug interactions, and drug toxicity can depend on racial and ethnic characteristics with the population frequencies of the many polymorphic genes and the expression of the metabolizing enzymes. Pharmacogenetics focuses primarily on genetic polymorphisms (mutations) responsible for interindividual differences in drug metabolism and disposition. Genotype-phenotype correlation studies have validated that inherited mutations result in two or more distinct phenotypes causing very different responses following drug administration. The genes encoding for CYP2A6, CYP2C9, CYP2C19, and CYP2D6 are functionally polymorphic; therefore, at least 30% of P450-dependent metabolism is performed by polymorphic enzymes. For example, mutations in the CYP2D6 gene result in poor, intermediate, or ultrarapid metabolizers of more than 30 cardiovascular and central nervous system drugs. Thus, each of these phenotypic subgroups experiences different responses to drugs extensively metabolized by CYP2D6 pathway ranging from severe toxicity to complete lack of efficacy. For example, ethnic specificity has been observed with the sensitivity of the Japanese and Chinese to ethanol as compared to Caucasians, CYP2C19 polymorphism (affects ~20% of Asians and ~3% of Caucasians) and the variable metabolism of omeprazole (proton pump inhibitor) and antiseizure drugs, and the polymorphic paraoxonase-catalyzed hydrolysis of the neurotoxic organophosphates and lipid peroxides (atherosclerosis).

2.Physiologic factors. Age is a factor as both very young and old have impaired metabolism. Hormones, sex differences, pregnancy, changes in intestinal micro-flora, diseases (espeically those involving the liver), and nutritional status can also influence drug and xenobiotic metabolism.

Beause the liver is the principal site for xenobiotic and drug metabolism, liver disease can modify the pharmacokinetics of drugs metabolized by the liver. Several factors identified as major determinants of the metabolism of a drug in the diseased liver are:

  • the nature and extent of liver damage
  • hepatic blood flow
  • the drug involved
  • the dosage regimen
  • the degree of participation of the liver in the pharmacokinetics of the drug

Liver disease affects the elimination half-life of some drugs but not of others, although all undergo hepatic biotransformation. Some results have shown that the capacity for dug metabolism is impaired in chronic liver disase, which could lead to drug overdosage. Consequently, as a result of the unpredictability of drug effects in the presence of liver disorders, drug therapy in these circumstances is complex, and more than usual caution is needed.

Substances influencing drug and xenobiotic metabolism (other than enzyme inducers) include lipids, proteins, vitamins, and metals. Dietary lipid and protein deficiencies diminish microsomal drug-metabolizing activity. Protein deficiency leads to reduced hepatic microsomal protein and lipid metabolism; oxidative metabolism is decreased due to an alteration in endoplasmic reticulum (ER) membrane permeability affecting electron transfer. In terms of toxicity, protein deficiency would increase the toxicity of drugs and xenobiotics by reducing their oxidative microsomal metabolism and clearance from the body.

3.Pharmacodynamic factors. Dose, frequency, and route of administration, plus tissue distribution and protein binding of a drug, affect its metabolism.

4.Environmental factors. Competition of ingested environmental substances with other drugs and xenobiotics for metabolizing enzymes, and poisoning of enzymes by toxic chemicals such as carbon monoxide or pesticide synergists alter metabolism. Induction of enzyme expression (in which the number of enzyme molecules is increased, while the activity is constant) by other drugs and xenobiotics is another consideration.

Such factors (genetic, physiologic, pharmacodynamic, and environmental factors) can change not only the kinetics of an enzyme reaction but also the whole pattern of metabolism, thereby altering bioavailability, pharmacokinetics, pharmacologic activity, or toxicity of a xenobiotic.

How Pharmacogenetics Affects Drug Therapy

March 29, 2016 Pharmacogenetics No comments , , , ,

Polymorphisms of genes can affect drug therpay in three ways: polymorphisms in genes for drug-metabolizing enzymes, polymorphisms in genes encoding for drug transporters, and polymorphisms in genes encoding for drug targets.

Polymorphisms in Genes for Drug-Metabolizing Enzymes

Polymorphisms in the drug-metabolizing enzymes represent the first recognized and, so far, the most documented examples of genetic variants with consequences in drug response and toxicity. The major phase I enzymes are the CYP superfamily of isoenzymes. N-acetyltransferase, uridine diphosphate glucuronosyltransferase (UGT), and glutathione S-transferase are examples of phase II metabolizing enzymes that exhibit genetic polymorphisms. Thiopurine S-methyltransferase (TPMT) and dihydropyrimidine dehydrogenase (DPD) are examples of nucleotide base-metabolizing enzymes.

Polymorphisms in Drug Transporter Genes

Certain membrane-spanning protein facilitate drug transport across the gastrointestinal tract, drug excretion into the bile and urine, drug distribution across the blood-brain barrier, and drug uptake into target cells. Genetic variations for drug transport proteins may affect the distribution of drugs that are substrates for these proteins and alter drug concentrations at their therapeutic sites of action.

Polymorphisms in Drug Target Genes

Genetic polymorphisms occur commonly for drug target proteins, including receptors, enzymes, ion channels, and intracellular signaling proteins. Drug target genes may work in concert with genes that affect pharmacokinetic properties (i.e., genes for drug transporters and drug-metabolizing enzymes) to contribute to overall drug response. These drug targets include receptors, enzymes, intracellular signaling proteins, and ion channels.

Disease-Associated Genes

Numerous genes have been correlated with disease outcomes, and many of these have been found subsequently to influence response to pharmacologic disease management. These gene-drug response associations often occur despite the lack of a direct effect on pharmacokinetic or pharmacodynamic drug properties.