CYP2C9, CYP2C19, ABCB1 (MDR1) genetic polymorphisms and phenytoin metabolism in a Black Beninese population

Abstract

The genetically polymorphic cytochrome P450 2C9 (CYP2C9) metabolizes many important drugs. Among them, phenytoin has been used as a probe to determine CYP2C9 phenotype by measuring the urinary excretion of its major metabolite, S-enantiomer of 5-(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH). Phenytoin pharmacokinetic is also dependent on the activity of CYP2C19 and p-glycoprotein (ABCB1). To determine the influence of CYP2C9, CYP2C19 and ABCB1 genetic polymorphisms on phenytoin metabolism in a Black population, 109 healthy Beninese subjects received a single 300 mg oral dose of phenytoin. Blood was drawn 4 h after drug intake and urine was collected during the first 8 h. Plasma phenytoin and urine S- and R-enantiomers of p-HPPH were determined by high-performance liquid chromatography. Urinary excretion of (S)-p-HPPH [defined as urinary volumex(S)-p-HPPH urinary concentration] and PMR (defined as the ratio of p-HPPH in urine to 4 h phenytoin plasma concentration), both markers of CYP2C9 activity, were used to determine the functional relevance of new variants of CYP2C9 (*5, *6, *8, *9 and *11) in this population. Plasma phenytoin concentration was significantly associated with ABCB1 haplotype/genotype (P=0.05, Kruskal-Wallis test) and levels increased significantly in the genotype order: wild-type, T3421A and Block-2 genotypes (P=0.015, Jonckheere-Terpstra test). Urinary excretion of (S)-p-HPPH and PMR were significantly associated with the CYP2C9 genotype (P=0.001, analysis of variance (ANOVA) and P<0.0001, Kruskal-Wallis test, respectively) and decreased in the order: CYP2C9*1/*1, CYP2C9*1/*9, CYP2C9*9/*9, CYP2C9*1/*8, CYP2C9*8/*9, CYP2C9*9/*11, CYP2C9*1/*5, CYP2C9*6/*9, CYP2C9*1/*6, CYP2C9*8/*11, CYP2C9*5/*8 and CYP2C9*5/*6 (P<0.001, Jonckheere-Terpstra test). A combined analysis of CYP2C9, 2C19 and ABCB1 revealed that only ABCB1 predicted phenytoin concentration at 4 h and explained 8% of the variability (r=0.08, P=0.04). On the other hand, only CYP2C9 was predictive for the urinary excretion of (S)-p-HPPH and PMR (r=0.21, P=0.001 and r=0.25, P<0.001, respectively). Furthermore, significant relation was found between urinary excretion of (R)-p-HPPH and CYP2C9 genotype (P=0.035) and levels significantly increased in the genotype order: CYP2C9*1/*9, CYP2C9*1/*1, CYP2C9*9/*11, CYP2C9*1/*8 and CYP2C9*1/*5 (P<0.001, Jonckheere-Terpstra test). In summary, the present study demonstrates that, in a Black population, CYP2C9*5, *6, *8 and *11 variants, but not CYP2C9*9, are associated with a decreased phenytoin metabolism. The data also confirm the limited contribution of MDR1 gene to inter-individual phenytoin pharmacokinetic variation.

Effects of Cytochrome P450 2C9 Polymorphism on Bosentan Metabolism

“…Our investigation showed that CYP2C9*3 demonstrated significantly higher intrinsic clearance of BOS compared with wild type. Blaisdell et al (2004) demonstrated that CYP2C9*8 (R150H) exhibited a significantly increased catalytic activity in tolbutamide metabolism compared with wild-type CYP2C9*1, but Allabi et al (2005aAllabi et al ( , 2012 found CYP2C9*8 to be associated with lower clearance for phenytoin and warfarin. In the present study, we found that CYP2C9*8 showed significant decrement in V max (14.3%), which caused a lower clearance rate for BOS.…”

In vitro functional characterization of 37 CYP2C9 allelic isoforms found in Chinese Han population

“…However, there are limited and confusing data regarding the functional significance of these alleles. For example, CYP2C9.8 reportedly increases the metabolism of tolbutamide in vitro [23] , but reduces the metabolism of phenytoin and warfarin in vivo and/or in vitro [24,25] . Our data revealed that the CYP2C9.8 variant significantly reduced the intrinsic clearance value, while the CYP2C9.11 variant has no effect on the enzymatic activity toward tolbutamide in vitro ( Table 1).…”

Population pharmacokinetics of valproate in Mexican children with epilepsy

“…Some of those CYPs exist in the form of genetic variants, which may also affect the plasma concentrations and the exposure to antiepileptic drugs. The variability of kinetic parameters of antiepileptic drugs has been reported in different populations [7][8][9][10][11][12]. There are studies on the kinetic behavior of VPA and the factors that can modify it [13][14][15][16][17].…”