Pharmacokinetic consequences of CYP2D6 genotypes with emphasis on gene duplication/amplification

Abstract

The relationship between the major Caucasian and Oriental CYP2D6 genotypes and the disposition of two CYP2D6 substrates nortriptyline and debrisoquine was investigated.

Caucasians with 0, 1, 2, 3/4 and 13 functional CYP2D6-genes as well as Chinese and Korean subjects homo- and heterozygous for the CYP2D6*1 and CYP2D6*10 alleles were included. Single oral doses of 25 mg nortriptyline were given to all subjects except for ultrarapid metabolisers who were given a 50 mg dose to ensure accurate measurements of drug concentrations. Except for the Chinese all subjects also were given a single oral dose of 20 mg debrisoquine at a separate occasion. A very clear relationship between the number of functional CYP2D6 genes and the clearance of nortriptyline and debrisoquine and their metabolites was shown in Caucasians. The 0-96 hr mean overall urinary recovery of debrisoquine and its metabolites decreased with increasing number of functional genes. Renal clearance of debrisoquine decreased with the time after dose intake and also with the increasing number of functional genes. Significant differences in the kinetics of nortriptyline were shown between Chinese homozygous for CYP2D6*10 and those heterozygous or homozygous for the functional wildtype allele (*1). Koreans heterozygous for the CYP2D6*1 and *10 genes were shown to have similar capacity to metabolise debrisoquine and nortriptyline as compared to individuals homozygous for the CYP2D6*1 gene among both Koreans and Caucasians. When present in only one copy in the CYP2D6 locus, the CYP2D6*10 allele only has a marginal decreasing effect on the CYP2D6 enzyme activity. However, when present in two copies the decreasing effect on the enzyme is more pronounced. Five Caucasians with three or more functional CYP2D6 genes and a metabolic ratio (MR) of debrisoquine < 0. 15 received single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after the quinidine dose, 10 mg oral debrisoquine was given, urine was collected for 6 hours and debrisoquine MRs were calculated. A dose-effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1-2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while subjects with 13 functional genes required about 80 mg of quinidine.

We conclude that the number of functional CYP2D6 genes, and especially the presence of multiple functional CYP2D6-genes is of quantitative importance for the pharmacokinetics of drugs, whose metabolism is to a major extent catalysed by CYP2D6. Ultrarapid metabolisers may develop low plasma concentrations and show poor response or "therapy resistance" due to inadequate drug plasma concentrations despite normal or high doses of the drug assuming the parent compound is active. Such patients may also produce large amounts of metabolite(s), which, in case they are pharmacologically active, may contribute to the clinical effects of the parent compound. Metabolites may also produce toxicological effects or undesirable side-effects. The CYP2D6*10 allele in Orientals is associated with higher plasma levels of nortriptyline compared with the CYP2D6*1 allele due to an impaired metabolism. However, heterozygosity for CYP2D6*10 gene seems to decrease the CYP2D6-dependent elimination of nortriptyline and debrisoquine to only a limited degree. Further studies in Oriental subjects homozygous for CYP2D6*10 allele are required to fully elucidate the pharmacokinetic consequences of the CYP2D6 genotype in Orientals.

The utilisation of drugs may be improved and made more rational by using both therapeutic drug monitoring, pheno- and genotyping tests to establish individualised dosage strategies. Further prospective clinical studies of adverse drug reactions, drug toxicity and therapeutic failure in clinical evaluation of the consequences of different genotypes/phenotypes are required to improve such an adjustment of drug doses to the individual metabolic capacity.