Effects of CYP2C9 polymorphisms on the pharmacokinetics of R- and S-phenprocoumon in healthy volunteers

Abstract

CYP2C9 catalyses the biotransformation of the oral anticoagulants S-warfarin and R- and S-acenocoumarol. According to data obtained in vitro, phenprocoumon is also metabolized by CYP2C9 but the impact of the CYP2C9 polymorphism on phenprocoumon pharmacokinetics has not been studied. Twenty-six healthy heterozygous and homozygous carriers of the CYP2C9 alleles *1 (wild-type), *2 (Arg144Cys), and *3 (Ile359Leu) received a single oral dose of 12 mg of racemic phenprocoumon. Plasma and 12 h urine concentrations of both enantiomers and their monohydroxylated metabolites were measured by high-performance liquid chromatography with mass spectrometry detection. No significant effect of the CYP2C9 variants *2 and *3 on R-phenprocoumon pharmacokinetic parameters was detected, but S-phenprocoumon clearance tended to decrease with increasing number of CYP2C9*2 and *3 alleles. The ratios of S- to R-phenprocoumon plasma clearances were higher with a median of 0.95 in carriers of *1/*1 versus 0.65 in *3/*3 (P < 0.001 for trend). Plasma and urine concentrations of 4'-, 6- and 7-hydroxyphenprocoumon were significantly lower in homozygous carriers of the CYP2C9*2 and *3 variants compared to CYP2C9*1/*1. Carriers of CYP2C9*3/*3 had a median AUC of (R,S) 7-OH-phenprocoumon of only approximately 25% compared to the wild-type genotype. The AUC of (R,S) 6-OH-phenprocoumon was only approximately 50% in CYP2C9*3/*3 compared to the homozygous wild-type genotype. In conclusion, carriers of CYP2C9*2 and *3 alleles had a lower metabolic capacity regarding phenprocoumon hydroxylation than those with CYP2C9*1/*1. However, regarding phenprocoumon hydroxylation CYP2C9 genotypes had only marginal effects on S- and R-phenprocoumon total clearance in healthy volunteers.

Pharmacogenetics, Drug-Metabolizing Enzymes, and Clinical Practice

“…These discrepancies could relate to variable study design. For example, the minor effect seen in the single-dose study could partly relate to an inadequate sampling period (144 h), which was comparable with the estimated half-lives of S-and R-phenprocoumon (Kirchheiner et al, 2004d).…”

“…Phenprocoumon undergoes a large proportion of elimination via alternative pathways (e.g., renal and CYP3A4) (Toon et al, 1985;Ufer et al, 2004), so any relationship with the CYP2C9 genotype may be less important than for warfarin or acenocoumarol. After a single dose, a trend for decreased Sphenprocoumon clearance was seen with increasing number of CYP2C9 variant alleles in healthy subjects (Kirchheiner et al, 2004d). In two patient studies there was a 2-to 3-fold increased risk of bleeding or overanticoagulation (INR Ͼ6.0) in carriers of CYP2C9 variants (Hummers-Pradier et al, 2003;Schalekamp et al, 2004a).…”

Genetic determinants of acenocoumarol and phenprocoumon maintenance dose requirements

“…Furthermore a significant portion of the drug is excreted in an unchanged form in bile and urine, while clearance of warfarin and AC occurs almost completely by their metabolism [28]. Although associations of CYP2C9 sequence variations with reduced PC 7-hydroxylation have been shown in vitro [36] and in vivo [37], the clinical impact of CYP2C9 variant alleles on PC dosing requirements is still controversial. Visser et al failed to reveal significant differences in dose requirements between carriers of the CYP2C9*2 and CYP2C9*3 allele(s) compared to wild-type subjects in a population-based cohort from the Rotterdam Study [38].…”

Evidence for immunological (allergic) mechanisms in a subgroup of patients with phenprocoumon-induced liver disease

“…A change in the antigenicity of hepatocytes caused by antigen expression of coumarin metabolites must be considered [3,8,9,31]. Phenprocoumon is highly protein bound and hydroxylated and conjugated in the liver [32][33][34][35][36]. Cytochrome P450 (CYP) 2C9 and CYP3A are the major enzymes involved in the hepatic metabolism of phenprocoumon [32,33,37].…”