Genetic Polymorphisms of Metabolic Enzymes and the Pharmacokinetics of Indapamide in Taiwanese Subjects

Abstract

Abstract. To understand the genetic makeup and impact on pharmacokinetics (PK) in the Taiwanese population, we analyzed the pharmacogenetic (PG) profile and demonstrated its effects on enzyme metabolism using indapamide as an example. A multiplex mass spectrometry method was used to examine the single nucleotide polymorphism (SNP) profile of eight major phases I and II metabolic enzymes in 1,038 Taiwanese subjects. A PG/PK study was conducted in 24 healthy subjects to investigate the possible effects of 28 SNPs on drug biotransformation. Among the genetic profile analyzed, eight SNPs from CYP2A6, CYP2C19, CYP2D6, CYP2E1, CYP3A5, and UGT2B7 showed higher variant frequencies than those previously reported in Caucasians or Africans. For instance, we observed 14.7% frequency of the SNP rs5031016 (I471T) from CYP2A6 in Taiwanese, whereas 0% variation was reported in Caucasians and Africans. The PG/PK study of indapamide demonstrated that the polymorphic SNPs CYP2C9 rs4918758 and CYP2C19 rs4244285 appeared to confer lowered enzyme activity, as indicated by increased C max (25%∼64%), increased area under the plasma level-time curves (30∼76%), increased area under the time infinity (43%∼80%), and lower apparent clearance values than PK for wild-type indapamide. Our results reinforce the biochemical support of CYP2C19 in indapamide metabolism and identify a possible new participating enzyme CYP2C9. The PG/PK approach contributed toward understanding the genetic makeup of different ethnic groups and associations of enzymes in drug metabolism. It could be used to identify two genetic markers that enable to differentiate subjects with varied PK outcomes of indapamide.

Genotyping of CYP2C19 polymorphisms and its clinical validation in the ethnic Arab population

“…This finding also does not seem to be in concordance with the available literature on the distribution of these two variants in other ethnic groups. However, like the CYP2C19*17 , the distribution of particularly the CYP2C19* 2 is also known to vary among ethnic populations [41,49–58]. For example, a study by the European Atherosclerosis Research Study showed a higher prevalence of increased on‐treatment platelet reactivity to clopidogrel corresponding to a higher CYP2C19*2 allele carrier status in African‐American patients undergoing PCI compared with their white counterparts, leading to the conclusion that the AA genotype predisposed individuals to a higher risk of ischaemic complications in the former group [59].…”

Influence of CYP2C9 Genetic Polymorphisms on the Pharmacokinetics of Losartan and Its Active Metabolite E-3174: A Systematic Review and Meta-Analysis

“…For torsemide, it was shown that CYP2C9*3 resulted in lower oral clearance and metabolite formation clearance [ 33 ]. In the study of Wang et al, patients with homozygous variants of CYP2C9 rs4918758, which showed lowered CYP2C9 activity, had higher C max and AUC and lower clearance of indapamide [ 34 ]. As CYP2C9 is involved in the metabolism of several antihypertensive agents, CYP2C9 loss-of-function alleles may increase the parent drug level.…”

Pharmacokinetic Properties of Two Erlotinib 150 mg Formulations with a Genetic Effect Evaluation in Healthy Korean Subjects

“…There are numerous studies demonstrating that genetic differences are associated with different metabolic activity of chemicals, including drugs [44][45][46]. As noted above, erlotinib is metabolized by CYP3A4, CYP1A2 and CYP1A1.…”