Ethnicity is an important demographic variable contributing to interindividual variability in drug metabolism and response. In this rapidly expanding research area many genetic factors that account for the effects of ethnicity on pharmacokinetics, pharmacodynamics, and drug safety have been identified. This review focuses on recent developments that have improved understanding of the molecular mechanisms responsible for such interethnic differences. Genetic variations that may provide a molecular basis for ethnic differences in drug metabolizing enzymes (CYP 2C9, 2C19, 2D6, and 3A4), drug transporter (P-glycoprotein), drug receptors (adrenoceptors), and other functionally important proteins (eNOS and G proteins) are discussed. A better understanding of the molecular basis underlying ethnic differences in drug metabolism, transport, and response will contribute to improved individualization of drug therapy.

Molecular basis of ethnic differences in drug disposition and response.

Voriconazole is a new triazole antifungal agent with potent, wide-spectrum activity. Its pharmacokinetics and metabolism have been studied in mouse, rat, rabbit, dog, guinea pig, and humans after single and multiple administration by both oral and intravenous routes. Absorption of voriconazole is essentially complete in all species. The elimination of voriconazole is characterized by non-linear pharmacokinetics in all species. Consequently, pharmacokinetic parameters are dependent upon dose, and a superproportional increase in area under the curve is seen with increasing dose in rat and dog toxicology studies. Following multiple administration, there is a decrease in systemic exposure. This is most pronounced in mouse and rat, less so in dog, and not observed in guinea pig or rabbit. Repeat-dose toxicology studies in mouse, rat, and dog have demonstrated that induction of cytochrome P450 by voriconazole (autoinduction of metabolism) is responsible for the decreased exposure in these species. Autoinduction of metabolism is not observed in humans, and plasma steady-state concentrations remain constant with time. Voriconazole is extensively metabolized in all species. The major pathways in humans involve fluoropyrimidine N-oxidation, fluoropyrimidine hydroxylation, and methyl hydroxylation. Also, N-oxidation facilitates cleavage of the molecule, resulting in loss of the fluoropyrimidine moiety and subsequent conjugation with glucuronic acid. Major pathways are represented in animal species. The major circulating metabolite in rat, dog, and human is the N-oxide of voriconazole. It is not thought to contribute to efficacy since it is at least 100-fold less potent than voriconazole against fungal pathogens in vitro.

The disposition of voriconazole in mouse, rat, rabbit, guinea pig, dog, and human.

Interethnic differences in drug-metabolising capacity may be substantial, and they are sufficiently frequent to warrant attention. Such differences may consist of different mean values of quantitative traits in separate populations, or of different frequency distributions as produced by the occurrence of genetic enzyme variants. The collection of population data requires the investigation of substantial numbers of subjects. This may be no problem if drug-metabolising enzymes occur in blood or are sufficiently stable in their tissues to allow investigation in vitro. However, if investigations require the use of probe drugs, new efforts are needed to adapt pharmacokinetic methods to make them suitable for population studies. This development of methods is further called for because genetic variants seem to be more easily detected through the assessment of particular metabolites than through the determination of pharmacokinetic parameters of the parent drug. Many studies with probe drugs comparing different populations have given results that are equivocal in terms of the nature-nurture interplay. However, a set of data with antipyrine has pointed to environmental factors as the principal determinant of differences in metabolising capacity, while data with debrisoquine have indicated monogenically controlled variation of one facet of the cytochrome P-450 system. In several instances, statistically significant differences between population means have been established by testing small numbers of subjects, numbers insufficient to establish distribution patterns that would allow the recognition of genetic polymorphism. The populations studied range from Greenlanders to South African Blacks, but most comparisons pertain to Caucasians and Orientals.

Ethnic Differences in Drug Metabolism

Kinetics of intravenously administered heparin in normal humans

The rate of disappearance of diphenylhydantoin from plasma was studied in 70 healthy volunteers by giving them 100 mg. orally 3 times daily for 3 days and measuring the plasma diphenylhydantoin concentration for 4 consecutive days after the last dose of the drug. The mean plasma half‐life was 22.0 ± 9.0 hours and the difference between that of Negro and Caucasian males, 26.5 and 18.5 hours, respectively, was Significant. Dose dependency of the half‐life was demonstrated in 10 subjects studied. The decline in plasma diphenylhydantoin concentration in many subfects was not exponential and the disappearance of the drug from plasma was not always a first‐order process. The diphenylhydantoin half‐life in some subjects was shorter after long‐term administration than after short‐term administration of the drug. Saturation, autoinduction, or product inhibition, singly or in combination, of the drug‐metabolizing enzyme system are possible mechanisms involved in the dose dependency and nonexponential decline of plasma diphenylhydantoin concentration.

The rate of decline of diphenylhydantoin in human plasma

The rate of disappearance of diphenylhydantoin (DPH) has been measured in mice given different doses ranging from 125 g to 1250 g. The biologic half-life (T½) of DPH in mice increases as the dose increases and ranges from 5 hr in mice given 125 g each to 16 hr in mice given 1 mg each. The rate of disappearance of DPH does not follow first-order kinetics in five of the six doses studied. An increase in the rate of disappearance of DPH in mice given 1 mg occurs after 16 hr. The increase in rate is associated with a stimulation of the drug-metabolizing liver microsomal enzymes. Treatment of mice with a single dose of 1 mg of DPH results in a significant increase in liver microsomal protein, zoxazolamine hydroxylase activity and cytochrome P450 content. Treatment of mice with 1 mg of DPH daily for 4 days also increases liver weight and liver protein and causes a proliferation of the smooth endoplasmic reticulum. A subsequent dose of 1 mg of DPH is metabolized more rapidly in these mice (T½ = 7.5 hr) compared with controls ( T½ = 16 hr), and the disappearance more closely follows first-order kinetics. Four days of treatment of each mouse with 1 mg daily of DPH results in a reduction in hexobarbital sleeping time and zoxazolamine paralysis time 40 hr after the last injection of DPH. There is also increased hexobarbital oxidase activity and zoxazolamine hydroxylase activity in liver microsomes of these mice. SKF 525-A (β-diethylaminoethyl diphenylpropyl acetate) (50 mg/kg) and cycloheximide (100 mg/kg) pretreatment decreases the rate of disappearance of DPH.

Studies on the metabolism of diphenylhydantoin in mice

Mice pretreated for 4 days with a series of corm pounds were given 1 mg of diphenylhydantoin i.p. The quantity of diphenyihydantoin recovered at the end of 17 hr was significantly less in some of the pretreated animals compared with the controls. Compounds which were effective included a group of substituted diphenyl-piperazine agents (hydroxyzine, cyclizine, chlorcyclizine, meclizine and norchlorcyclizine), phenobarbital and diphenyihydantoin itself. 3-Methylcholanthrene and 3,4-benzpyrene, which were given as a single dose 24 hr before the diphenylhydantoin, were ineffective. Hydroxyzine pretreatment increased liver weight and total liver protein, and electron microscopy of the livers showed an increase in the smooth endoplasmic reticulum. Hydroxyzine pretreatment reduced hexobarbital sleeping time and zoxazolamine paralysis time in the mice. In vitro studies using the supernatant fraction containing the microsornes obtained after centrifugation at 9000 x g for 20 min showed an increased metabolism of hexobarbital and zoxazolamine. Human volunteers showed no change in diphenyihydantoin plasma half-life after 1 month of treatment with hydroxyzine.

Nicholas Gerber

Papers

The rate of decline of diphenylhydantoin in human plasma

Studies on the metabolism of diphenylhydantoin in mice

The effect of diphenyl-piperazine compounds and other agents on diphenylhydantoin, zoxazolamine and hexobarbital metabolism