The Impact of Certain Pharmacogenetic Differences on the Metabolism of Antiretroviral Drugs Used in A Black South African Population.

IF 2.1 4区医学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY

Current drug metabolism Pub Date : 2023-01-01 DOI:10.2174/0113892002255240231117072211

Riaan Reay, Michelle Viljoen, Malie Rheeders

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Abstract

Background: Genetic polymorphism of drug-metabolising enzymes and transporters may influence the effect and toxicity of antiretroviral drugs.

Objectives: To determine and compare the minimum allele frequency of 20 single nucleotide polymorphisms (SNPs) with possible involvement in the metabolism of the antiretroviral drugs with other populations. To investigate the influence of these variants on Reverse transcriptase, Protease and Integrase strand transfer inhibitor drugs.

Method: DNA samples were collected from 1489 subjects. All SNPs with a gene call score of > 0.6 were selected for genotyping. The R package calculated call rates, MAF and Hardy-Weinberg equilibrium (HWE), test p-values, and Chi-squared analysis were performed on the data. The Fisher's exact test compared the allele frequencies between the populations.

Results: The highest similarities in minimum allele frequency (MAF) were between the Prospective Urban and Rural Epidemiological group (PURE), a Black population in South Africa, and the Yoruba and Luhya populations in Africa. The following SNPs were identified with a possible effect on metabolism: CYP2B6 rs28399494 (MAF 11%) is indicated in the toxicity of Efavirenz and Nevirapine. CYP3A5 rs776746 (MAF 17%) and CYP3A4 rs2749674 (MAF 23%) both cause an increase in the metabolism of the protease inhibitors. The very low MAF values for both SCL01B1 rs4149056 (MAF 0.6%) and ABCC rs717620 (MAF 2.8%) are indications that OATP1B1 transport function and glomerular filtration tempo will not be compromised. The high MAF value of 30% for UGTA1 rs10929302 can result in hyperbilirubinemia, which can decrease the clearance of Dolutegravir.

Conclusion: These results show a possibility of kidney protection and an increase in bilirubin in this population.

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某些药理学差异对南非黑人人群抗逆转录病毒药物代谢的影响

背景:药物代谢酶和转运体的遗传多态性可能影响抗逆转录病毒药物的效果和毒性。目的:确定和比较可能参与抗逆转录病毒药物代谢的20个单核苷酸多态性(snp)的最小等位基因频率。探讨这些变异对逆转录酶、蛋白酶和整合酶链转移抑制剂药物的影响。方法:采集1489例受试者的DNA样本。选择所有基因呼唤评分> 0.6的snp进行基因分型。R包计算调用率，MAF和Hardy-Weinberg均衡(HWE)，检验p值，并对数据进行卡方分析。Fisher的精确测试比较了人群之间的等位基因频率。结果:最小等位基因频率(MAF)在前瞻性城乡流行病学组(PURE)、南非黑人人群和非洲约鲁巴和卢希亚人群之间相似性最高。以下snp可能对代谢产生影响:CYP2B6 rs28399494 (MAF 11%)与依非韦伦和奈韦拉平的毒性有关。CYP3A5 rs776746 (MAF 17%)和CYP3A4 rs2749674 (MAF 23%)均引起蛋白酶抑制剂代谢增加。SCL01B1 rs4149056 (MAF 0.6%)和ABCC rs717620 (MAF 2.8%)的MAF值都非常低，表明OATP1B1转运功能和肾小球滤过速度不会受到损害。UGTA1 rs10929302高达30%的MAF值可导致高胆红素血症，从而降低多路替韦的清除率。结论:这些结果表明在该人群中可能有肾保护作用和胆红素升高。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current drug metabolism 医学-生化与分子生物学

CiteScore

4.30

自引率

4.30%

发文量

审稿时长

4-8 weeks

期刊介绍： Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism, pharmacokinetics, and drug disposition. The journal serves as an international forum for the publication of full-length/mini review, research articles and guest edited issues in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the most important developments. The journal covers the following general topic areas: pharmaceutics, pharmacokinetics, toxicology, and most importantly drug metabolism. More specifically, in vitro and in vivo drug metabolism of phase I and phase II enzymes or metabolic pathways; drug-drug interactions and enzyme kinetics; pharmacokinetics, pharmacokinetic-pharmacodynamic modeling, and toxicokinetics; interspecies differences in metabolism or pharmacokinetics, species scaling and extrapolations; drug transporters; target organ toxicity and interindividual variability in drug exposure-response; extrahepatic metabolism; bioactivation, reactive metabolites, and developments for the identification of drug metabolites. Preclinical and clinical reviews describing the drug metabolism and pharmacokinetics of marketed drugs or drug classes.