Department of Pharmacology and Clinical Pharmacy, School of Pharmacy, College of Health Sciences, Addis Ababa University, P.O Box 1176, Addis Ababa, Ethiopia.
CICAB Clinical Research Centre, Extremadura University Hospital & Medical School, E-06071, Badajoz, Spain.
Sci Rep. 2018 Aug 24;8(1):12726. doi: 10.1038/s41598-018-31191-1.
In a one-way cross-over study, we investigated the effect of Khat, a natural amphetamine-like psychostimulant plant, on catalytic activities of five major drug-metabolizing cytochrome P450 (CYP) enzymes. After a one-week Khat abstinence, 63 Ethiopian male volunteers were phenotyped using cocktail probe drugs (caffeine, losartan, dextromethorphan, omeprazole). Phenotyping was repeated after a one-week daily use of 400 g fresh Khat leaves. Genotyping for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A5 were done. Urinary cathinone and phenylpropanolamine, and plasma probe drugs and metabolites concentrations were quantified using LC-MS/MS. Effect of Khat on enzyme activities was evaluated by comparing caffeine/paraxanthine (CYP1A2), losartan/losartan carboxylic acid (CYP2C9), omeprazole/5-hydroxyomeprazole (CYP2C19), dextromethorphan/dextrorphan (CYP2D6) and dextromethorphan/3-methoxymorphinan (CYP3A4) metabolic ratios (MR) before and after Khat use. Wilcoxon-matched-pair-test indicated a significant increase in median CYP2D6 MR (41%, p < 0.0001), and a marginal increase in CYP3A4 and CYP2C19 MR by Khat. Repeated measure ANOVA indicated the impact of CYP1A2 and CYP2C19 genotype on Khat-CYP enzyme interactions. The median MR increased by 35% in CYP1A2*1/*1 (p = 0.07) and by 40% in carriers of defective CYP2C19 alleles (p = 0.03). Urinary log cathinone/phenylpropanolamine ratios significantly correlated with CYP2D6 genotype (p = 0.004) and CYP2D6 MR (P = 0.025). Khat significantly inhibits CYP2D6, marginally inhibits CYP3A4, and genotype-dependently inhibit CYP2C19 and CYP1A2 enzyme activities.
在一项单臂交叉研究中，我们研究了天然安非他命样兴奋剂阿拉伯茶对五种主要药物代谢细胞色素 P450（CYP）酶催化活性的影响。在一周的阿拉伯茶戒断后，63 名埃塞俄比亚男性志愿者使用鸡尾酒探针药物（咖啡因、洛沙坦、右美沙芬、奥美拉唑）进行表型分析。在一周每天使用 400 克新鲜阿拉伯茶叶后重复表型分析。进行 CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A5 的基因分型。使用 LC-MS/MS 定量测定尿中卡西酮和苯丙醇胺以及血浆探针药物和代谢物浓度。通过比较咖啡因/茶碱（CYP1A2）、洛沙坦/洛沙坦羧酸（CYP2C9）、奥美拉唑/5-羟奥美拉唑（CYP2C19）、右美沙芬/右旋美沙芬（CYP2D6）和右美沙芬/3-甲氧基吗啡烷（CYP3A4）代谢比（MR），评估阿拉伯茶对酶活性的影响。在使用阿拉伯茶前后。Wilcoxon 配对检验表明，CYP2D6 MR 中位数显著增加（41%，p<0.0001），CYP3A4 和 CYP2C19 MR 略有增加。重复测量方差分析表明 CYP1A2 和 CYP2C19 基因型对阿拉伯茶-CYP 酶相互作用的影响。CYP1A2*1/*1 携带者的 MR 增加 35%（p=0.07），有缺陷 CYP2C19 等位基因携带者的 MR 增加 40%（p=0.03）。尿中卡西酮/苯丙醇胺比值与 CYP2D6 基因型显著相关（p=0.004）和 CYP2D6 MR（P=0.025）。阿拉伯茶显著抑制 CYP2D6，轻度抑制 CYP3A4，并依赖于 CYP2C19 和 CYP1A2 基因型抑制酶活性。
