Genetic Polymorphisms In Drug Metabolism Research Articles

Ethnic factors in evaluation of drug efficacy and safety

Ethnic difference is considered to be a major barrier in world-wide drug development. There seem to be many ethnic factors, genetic, environmental and cultural differences. There exists genetic polymorphism in drug metabolism especially for N-acetylation, debrisoquine hydroxylation and S-mephenytoin hydroxylation. The frequency of slow acetylator, poor metabolizer of debrisoquine and S-mephenytoin are 10%, less than 1% and 20% in Japanese and 50%, 10% and 5% in Caucasians respectively. Clinical responses and adverse effect of drugs are associated with these phenotypes. A retrospective study was conducted to determine whether inter-ethnic pharmacokinetic difference is larger than intra-ethnic variability. Individual pharmacokinetic parameters for most drugs were found to be extremely variable, but similarities of pharmacokinetic parameters were observed for Cmax and AUC between Japanese and other races. The results suggest that intra-ethnic variability is larger than inter-ethnic difference. The knowledge of genetic polymorphisms must find its way into clinical practice in order to achieve rational drug therapy that is more effective and safer for the benefit of the patient.

Genetically determined adverse drug reactions involving metabolism.

Genetic factors represent an important source of interindividual variation in drug response. Relatively few adverse drug effects with a pharmacodynamic basis are known, and most of the well characterised inherited traits take the form of genetic polymorphisms of drug metabolism. Monogenic control of N-acetylation, S-methylation and cytochrome P450-catalysed oxidation of drugs can have important clinical consequences. Individuals who inherit an impaired ability to perform one or more of these reactions may be at an increased risk of concentration-related toxicity. There is a strong case for phenotyping before starting treatment with a small number of drugs that are polymorphically N-acetylated or S-methylated. However, the issue of clinical significance is perhaps most relevant for the debrisoquine oxidation polymorphism, which is mediated by cytochrome CYP2D6 and which determines the pharmacokinetics of many commonly used drugs. Phenotypic poor metabolisers of debrisoquine (8% of Caucasian populations) taking standard doses of some tricyclic antidepressants, neuroleptics or antiarrhythmic drugs may be particularly prone to adverse reactions. Similarly, clinically relevant drug interactions between these drugs and other substrates of cytochrome CYP2D6 may occur in the majority of the population who are extensive metabolisers. However, it is clear that in the majority of cases there is a need for controlled prospective studies to determine clinical significance. Accordingly, routine debrisoquine phenotyping or genotyping before beginning drug treatment is difficult to justify at present, although it may be helpful in individual cases. When prescribing drugs whose metabolism is polymorphic alone or in combination, careful titration of the dose in both phenotypic groups is prudent. In some cases it will be preferable to use alternative therapy to avoid the risk of adverse drug reactions.

Variations in Drug Metabolism Due to Genetic Polymorphism

Many genes which encode the enzymes responsible for drug metabolism show polymorphism, existing in different forms as a result of mutation. Some polymorphisms are trivial and the resulting enzyme is functionally and even structurally normal; others produce functionally abnormal or inactive enzymes. In this case, affected individuals may have an impaired ability to metabolise those drugs and toxic substances which require that enzyme to be eliminated from the body. Although polymorphisms of particular metabolic routes, e.g. hydrolysis and acetylation, had been known for some time, it was the discovery of those affecting oxidation pathways that brought a new dimension to the relevance of genetic polymorphism in drug metabolism. The most extensively studied is that regulating the oxidative metabolism of the antihypertensive drug debrisoquine, which is caused by the absence in the liver of a specific cytochrome P450 isozyme, P450IID6. More than 25 drugs, including antiarrhythmic agents and tricyclic antidepressants, are substrates of P450IID6, and their metabolism is affected by the debrisoquine oxidation polymorphism. As a consequence, individuals with this metabolic defect experience exaggerated pharmacological responses and adverse reactions when they are treated with standard dosages of these drugs. This polymorphism has also been considered a possible risk factor in certain human diseases, such as bladder and gastrointestinal tract cancers. However, the establishment of a relationship between the metabolism of a drug and the debrisoquine oxidation polymorphism should not lead to a discontinuation of its development or to its withdrawal from clinical use.

Genetic polymorphisms of drug metabolism*

The molecular mechanisms of 3 genetic polymorphisms of drug metabolism have been studied at the level of enzyme activity, enzyme protein and RNA/DNA. As regards debrisoquine/sparteine polymorphism, cytochrome P-450IID6 was absent in livers of poor metabolizers; aberrant splicing of premRNA of P-450IID6 may be responsible for this. Moreover, 3 mutant alleles of the P-450IID6 locus on chromosome 22 associated with the poor metabolizer phenotype were identified by Southern analysis of leucocyte DNA. The presence of 2 identified mutant alleles allowed the prediction of the phenotype in approximately 25% of poor metabolizers. The additional gene-inactivating mutations which are operative in the remainder of poor metabolizers are now being studied. Regarding mephenytoin polymorphism, although the deficient reaction, S-mephenytoin 4'-hydroxylation, has been well defined in human liver microsomes, the mechanism of this polymorphism remains unclear. All antibodies prepared to date against cytochrome P-450 fractions with this activity recognize several structurally similar enzymes and several cDNAs related to these enzymes have been isolated and expressed in heterologous systems. However, which isozyme is affected by this polymorphism is not known. As regards N-acetylation polymorphism, N-acetyltransferases have been purified from human liver, specific antibodies prepared; it was observed that immunoreactive N-acetyltransferase is decreased or undetectable in liver of "slow acetylators". Two genes that encode functional N-acetyltransferase were characterized. The product of one of these genes has identical activity and characteristics as the polymorphic liver enzyme. Cloned DNA from rapid and slow acetylator individuals has been analyzed to identify the structural or regulatory defect that causes deficient N-acetyltransferase.

Relevance of genetic polymorphism in drug metabolism in the development of new drugs

Drugs whose principal metabolic pathways are under polymorphic genetic regulation may show considerable interindividual pharmacokinetic variability. This could lead to clinically significant differences in the pharmacological responses of some patients and so might lead the pharmaceutical industry to stop development of the drug. This can be prevented and there are several measures that can be taken to avoid such premature termination of development. They include studies in vitro with human liver samples, and clinical pharmacological experiments designed specifically to examine possible genetic polymorphism in the disposition of the drug.

Chirality: pharmacokinetics and pharmacodynamics in 3 dimensions.

1. Biological macromolecules are able to distinguish between enantiomeric substrates. A three-point interaction between the drug enantiomers and the macromolecule (Easson-Stedman hypothesis) can frequently account for this selectivity. 2. Significant pharmacodynamic differences between enantiomers are more the rule than the exception. 3. Pharmacokinetic differences between enantiomers are, in general, not as great as the pharmacodynamic differences. However, stereoselective protein binding, metabolism and renal clearance are still very important aspects of understanding drug disposition and the time course of drug action. 4. There may be pharmacokinetic and pharmacodynamic enantiomer-enantiomer interactions. Consequently, the activity and disposition of a racemic drug may not be the simple sum of the activities and disposition of the individual enantiomers. 5. Enantiomers have been used as sensitive 3-dimensional probes to establish structure-activity relationships, to provide insights into genetic polymorphism of drug metabolism, and to provide insights into other aspects of drug disposition. 6. A need for a 3-dimensional understanding of pharmacodynamics and pharmacokinetics is implicit in the asymmetric nature of biological environments.

Genetic polymorphisms of drug metabolism. Possible implications during development.

Genetic polymorphisms of drug metabolism can affect phase I and phase II reactions. Polymorphisms of cytochrome P450 activity or inducibility have been implicated in drug toxicity and in cancerogenesis. Polymorphisms of the detoxification processes may be important in the appearance of adverse responses to conventional doses of drugs. Pharmacogenetics now opens new ways to investigate the relations between genetic factors, xenobiotics and teratogenesis.

Genetic polymorphism of drug metabolism.

Genetic polymorphism of drug metabolism.

The pharmacokinetics of bucindolol and its major metabolite in essential hypertension.

The pharmacokinetics of bucindolol and its major metabolite, 5-hydroxybucindolol, have been studied in eight patients with mild/moderate hypertension. The mean terminal elimination half-life of bucindolol following acute oral dosing was 8.0 +/- 4.5 h, while the elimination half-life of the metabolite was 0.15 +/- 0.13 h. Because of the large intraindividual variation in the pharmacokinetics of the drug and metabolite, no significant differences in the kinetics following acute or chronic dosing were seen. There was very wide interindividual variability in the pharmacokinetics of bucindolol and 5-hydroxybucindolol, and large interindividual differences in the metabolic profiles as assessed by the areas under drug and metabolite concentration-time curves. This latter observation might be associated with a genetic polymorphism of drug metabolism.

Toxicological implications of polymorphic drug metabolism.

The occurrence of genetic polymorphisms of drug metabolism means that populations contain subgroups (phenotypes) that differ sharply in their abilities to effect a number of metabolic reactions. Because of this, major interphenotype differences occur in responsiveness to drugs and toxic substances. The well established genetic polymorphisms of acetylation and hydrolysis illustrate the important association that exists between phenotype and propensity to develop toxic and exaggerated responses to some substances. Recently, for metabolic oxidation, a new genetic polymorphism of drug metabolism has been described and it promises to provide a better understanding of inter-individual variability in the metabolic handling of, and responsiveness to, drugs and toxic substances. The following effects of the polymorphism are described here: (a) its influence in determining variable presystemic metabolism and hence systemic drug availability; (b) its role in determining alternative toxic pathways of metabolism in individuals who have a genetically determined impairment of oxidative capacity and (c) its influence on the development of agranulocytosis associated with metiamide administration.

The N-oxidation of alkylhydrazines catalyzed by the microsomal mixed-function amine oxidase

Flavin-containing monooxygenase (FMO) oxygenates drugs and xenobiotics containing a “soft-nucleophile”, usually nitrogen or sulfur. FMO, like cytochrome P450 (CYP), is a monooxygenase, utilizing the reducing equivalents of NADPH to reduce 1 atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. FMO and CYP also exhibit similar tissue and cellular location, molecular weight, substrate specificity, and exist as multiple enzymes under developmental control. The human FMO functional gene family is much smaller (5 families each with a single member) than CYP. FMO does not require a reductase to transfer electrons from NADPH and the catalytic cycle of the 2 monooxygenases is strikingly different. Another distinction is the lack of induction of FMOs by xenobiotics.In general, CYP is the major contributor to oxidative xenobiotic metabolism. However, FMO activity may be of significance in a number of cases and should not be overlooked. FMO and CYP have overlapping substrate specificities, but often yield distinct metabolites with potentially significant toxicological/pharmacological consequences.The physiological function(s) of FMO are poorly understood. Three of the 5 expressed human FMO genes, FMO1, FMO2 and FMO3, exhibit genetic polymorphisms. The most studied of these is FMO3 (adult human liver) in which mutant alleles contribute to the disease known as trimethylaminuria. The consequences of these FMO genetic polymorphisms in drug metabolism and human health are areas of research requiring further exploration.