CYP2C9, CYP2C19, ABCB1 genetic polymorphisms and phenytoin plasma concentrations in Mexican-Mestizo patients with epilepsy

Abstract

We aimed to explore the possible influence of CYP2C9 (*2, *3 and IVS8-109 A>T), CYP2C19 (*2, *3 and *17) and ABCB1 (1236C>T, 2677G>A/T and 3435C>T) on phenytoin (PHT) plasma concentrations in 64 Mexican Mestizo (MM) patients with epilepsy currently treated with PHT in mono- (n=25) and polytherapy (n=39). Genotype and allele frequencies of these variants were also estimated in 300 MM healthy volunteers. Linear regression models were used to assess associations between the dependent variables (PHT plasma concentration and dose-corrected PHT concentration) with independent variables (CYP2C9, CYP2C19 and ABCB1 genotypes, ABCB1 haplotypes, age, sex, weight, and polytherapy). In multivariate models, CYP2C9 IVS8-109 T was significantly associated with higher PHT plasma concentrations (t(64)=2.27; P=0.03). Moreover, this allele was more frequent in the supratherapeutic group as compared with the subtherapeutic group (0.13 versus 0.03, respectively; P=0.05, Fisher's exact test). Results suggest that CYP2C9 IVS8-109 T allele may decrease CYP2C9 enzymatic activity on PHT. More research is needed to confirm findings.

Frequency of CYP2C9 (*2, *3 and IVS8‑109A>T) allelic variants, and their clinical implications, among Mexican patients with diabetes mellitus type 2 undergoing treatment with glibenclamide and metformin

“…A statistical comparison revealed that the frequency of CYP2C9*1 / *2 was, overall, 50% lower amongst patients with DMT2 compared with healthy individuals (6.5 vs. 9-16%; P<0.05) (data not shown) (42-45), whereas CYP2C9*2/*2 was 40% lower amongst the patients with DMT2 compared with healthy volunteers from northern Mexico (0.04 vs. 1.0%; P<0.05) (data not shown) (42-45). CYP2C9*1 / *3 was significantly different only amongst populations from Sonora, Mexico City and Guerrero (5 vs. 10%, 1% and 10%; P<0.05) (29,42-46) (data not shown).…”

“…IVS8-109T has already been observed amongst healthy volunteers, where it displays substantial interethnic variability (25). When comparing IVS8-109A>T variants from the studied Mexican patients with DMT2 with healthy individuals from different countries, including Sweden (25), Japan (46), Korea (25,47), Ecuador (26) and Mexico (29) itself, statistically significant differences were identified regarding the frequencies of A / T and T / T , and the prevalence of the alleles A and T in every case (P<0.05; Table V).…”

“…Differences between the drug response genes of healthy and diseased populations have been established (regarding efficacy or adverse reactions) (29). In the present study, there were significant differences between the Mestizo patients with DMT2 and healthy individuals from the Mexican population regarding *1 / *2 (P<0.05) (data not shown) and the distribution of variants *2 and *3 ; but there were also differences with respect to other Caucasian, Asian and Latin American populations regarding IVS8-109T , as its association with either slow or rapid CYP2C9 metabolism remains unclear.…”

“…This variant had not been described previously in any study on DMT2 populations. Only recently was it observed in healthy volunteers (n=300) and patients with epilepsy (n=64), where the T allele was less prevalent among the latter (29 vs. 19%; P=0.02) (29).…”

Precision medicine: does ethnicity information complement genotype-based prescribing decisions?

“…To complicate the matter further, the same intronic SNP has now been reported to lead to decreased metabolic activity towards phenytoin in Mexican Mestizo patients with epilepsy. 72 One study recently reported that a common variant of P450 Oxidoreductase gene ( POR*28 ) was associated with altered CYP2C9 activity in Swedish, but not Korean, healthy subjects. 73 Its impact was determined to be only minimal in a Spanish population.…”