Lammers Laureen A, Achterbergh Roos, de Vries Emmely M, van Nierop F Samuel, Klümpen Heinz-Josef, Soeters Maarten R, Boelen Anita, Romijn Johannes A, Mathôt Ron A A
Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
Departments of Hospital Pharmacy (L.A.L., R.A.A.M.), Medicine (R.A., J.A.R.), Endocrinology and Metabolism (E.M.d.V., F.S.v.N., M.R.S., A.B.), and Medical Oncology (H.-J.K.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Drug Metab Dispos. 2015 Jun;43(6):819-28. doi: 10.1124/dmd.114.062299. Epub 2015 Mar 20.
Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P < 0.001). In rats, short-term fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P < 0.05), and decreased the mRNA expression of the ortholog of CYP2C9 (P < 0.001) compared with the postabsorptive state. These results demonstrate that short-term fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.
实验研究表明，短期禁食会改变药物代谢。然而，短期禁食对人体药物代谢的影响尚需进一步研究。因此，本研究的目的是评估短期禁食（36小时）对细胞色素P450介导的药物代谢的影响。在一项随机交叉研究设计中，九名健康受试者分两次摄入了由五种细胞色素P450特异性探针药物组成的鸡尾酒（咖啡因（CYP1A2）、S-华法林（CYP2C9）、奥美拉唑（CYP2C19）、美托洛尔（CYP2D6）和咪达唑仑（CYP3A4））（一次是在过夜禁食后进行对照研究，另一次是在禁食36小时后）。采集血样，采用非线性混合效应模型进行药代动力学分析。此外，我们在Wistar大鼠中研究了短期禁食对与人类研究的五种细胞色素P450酶相对应的细胞色素P450同工型肝脏mRNA表达的影响。在健康受试者中，短期禁食使口服咖啡因清除率提高了20%（P = 0.03），使口服S-华法林清除率降低了25%（P < 0.001）。在大鼠中，与吸收后状态相比，短期禁食使人类CYP1A2、CYP2C19、CYP2D6和CYP3A4直系同源物的mRNA表达增加（P < 0.05），并使CYP2C9直系同源物的mRNA表达降低（P < 0.001）。这些结果表明，短期禁食以一种不均匀的模式改变细胞色素P450介导的药物代谢。因此，短期禁食是影响人体细胞色素P450介导的药物代谢的另一个因素。
