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.