Abstract
The pharmacokinetics of CYP2C9 substrates is characterized by substantial interethnic variability. The objective of the study was to compare CYP2C9 activity by using Phenytoin Metabolic Ratio (PMR) between Ethiopian and non-Ethiopian Jews. PMR was derived from the ratio of p-HPPH in 24 h urine collection to plasma phenytoin, 12 h (PMR24/12) or 24 h (PMR24/24) after the administration of 300 mg phenytoin. Analysis of CYP2C9*2, *3, *5, *6, *8, and *11 was carried by direct sequencing. PMR was significantly correlated with CYP2C9 genotype in both groups (p < 0.002). Mean PMR values were similar among Ethiopians and non-Ethiopians despite the fact that the fraction of non-carriers of CYP2C9 variant alleles was significantly different (85 vs. 53%, respectively, p < 0.001). However, among non-carriers of CYP2C9*2, *3, *5, *6, *8, and *11 variant alleles, PMR24/12 and PMR24/24 values were 30 and 34% greater respectively in the non-Ethiopians group (p < 0.001). In conclusion—CYP2C9 activity as measured by PMR is similar in Ethiopian and non-Ethiopian Jews. However, among non-carriers of CYP2C9 variant alleles accounting for 85% of Ethiopian Jews, CYP2C9 activity is decreased by approximately one third as compared with non-Ethiopian Jews. Unique genetic CYP2C9 polymorphisms occurring only in Ethiopians may account for this difference.
Highlights
The metabolism of approximately 50% of commonly used drugs is mediated by three members of the cytochrome P450 superfamily of oxidative enzymes, CYP3A4, CYP2D6 and CYP2C9 (Zanger and Schwab, 2013; Daly et al, 2017)
The in-vivo activity of CYP2C9 can be reliably derived from the molar ratio of urinary content of phenytoin and urine concentration of 5(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) excreted over 24 h to mid-interval phenytoin plasma concentration (i.e. PMR24/12) or to phenytoin plasma concentration 24 h after dosing (i.e. PMR24/24), normalized to the duration of urine collection, as published previously (Caraco et al, 2001)
The distribution of CYP2C9 genotypes was in accordance with Hardy-Weinberg equilibrium in both Ethiopian and non-Ethiopians (ChiSquare, goodness to fit, p > 0.3 and p > 0.8 respectively)
Summary
The metabolism of approximately 50% of commonly used drugs is mediated by three members of the cytochrome P450 superfamily of oxidative enzymes, CYP3A4, CYP2D6 and CYP2C9 (Zanger and Schwab, 2013; Daly et al, 2017). The purpose of the current study was to compare CYP2C9 genotype and activity as measured by using phenytoin as a probe drug between Ethiopian Jews and a control group consisting of non-Ethiopian Jews. Plasma concentration of phenytoin and urine concentration of 5(4-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) were measured by two separate high-performance liquid chromatography methods. The in-vivo activity of CYP2C9 can be reliably derived from the molar ratio of urinary content of (total) p-HPPH excreted over 24 h to mid-interval phenytoin plasma concentration (i.e. PMR24/12) or to phenytoin plasma concentration 24 h after dosing (i.e. PMR24/24), normalized to the duration of urine collection, as published previously (Caraco et al, 2001). Comparison of data between carriers of different genotypes (i.e. CYP2C9, rs12777823) within each ethnic group was performed using ANOVA followed by unpaired t-test. Statistical analysis was performed using the SPSS software package (IBM SPSS Statistics, version 23, Chicago IL, USA.) and p value of less than 0.05 was considered to denote statistical significance
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