Interindividual Variability in Cytochrome P450-Mediated Drug Metabolism

Abstract

The cytochrome P450 (P450) enzymes are the predominant enzyme system involved in human drug metabolism. Alterations in the expression and/or activity of these enzymes result in changes in pharmacokinetics (and consequently the pharmacodynamics) of drugs that are metabolized by this set of enzymes. Apart from changes in activity as a result of drug-drug interactions (by P450 induction or inhibition), the P450 enzymes can exhibit substantial interindividual variation in basal expression and/or activity, leading to differences in the rates of drug elimination and response. This interindividual variation can result from a myriad of factors, including genetic variation in the promoter or coding regions, variation in transcriptional regulators, alterations in microRNA that affect P450 expression, and ontogenic changes due to exposure to xenobiotics during the developmental and early postnatal periods. Other than administering a probe drug or cocktail of drugs to obtain the phenotype or conducting a genetic analysis to determine genotype, methods to determine interindividual variation are limited. Phenotyping via a probe drug requires exposure to a xenobiotic, and genotyping is not always well correlated with phenotype, making both methodologies less than ideal. This article describes recent work evaluating the effect of some of these factors on interindividual variation in human P450-mediated metabolism and the potential utility of endogenous probe compounds to assess rates of drug metabolism among individuals.

Fig. 1.

CYP2C19*35 and CYP2C19*2 (both with rs12769205) have REHH scores similar in magnitude to haplotypes associated with malaria resistance. (A) Structure of CYP2C19*1, CYP2C19*35, and CYP2C19*2 mRNAs and their haplotype frequency in Yorubans. (B) REHH scores for CYP2C19*2 and CYP2C19*35 and for two haplotypes, G6PD haplotype 8 and TNFSF5 haplotype 4, under positive natural selection for resistance to malaria. G6PD, glucose-6-phosphate dehydrogenase; REHH, relative extended haplotype homozygosity; TNFSF5, tumor necrosis factor receptor superfamily member 5; Yri, Yorubans.

Fig. 2.

Models of the short- and long-term effect of phenobarbital exposure in early life on drug metabolism in mouse liver. (A) Effect of different doses of phenobarbital in early life. (B) Effect of high doses of phenobarbital at different developmental ages.

Fig. 3.

Differential transcriptional regulation of CYP2D6 through modulation of SHP expression may explain part of interindividual variability in CYP2D6-mediated drug metabolism.

Fig. 4.

Workflow for global and targeted metabolomics analyses to determine biomarkers of P450 activity. CYP, cytochrome P450.