Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
CPT Pharmacometrics Syst Pharmacol. 2019 Aug;8(8):587-595. doi: 10.1002/psp4.12420. Epub 2019 Jun 9.
In adult patients after living-donor liver transplantation, postoperative days and the cytochrome P450 3A5 (CYP3A5) genotype are known to affect tacrolimus pharmacokinetics. In this study, we constructed a physiologically-based pharmacokinetic model adapted to the clinical data and evaluated the contribution of liver regeneration as well as hepatic and intestine CYP3A5 genotypes on tacrolimus pharmacokinetics. As a result, liver function recovered immediately and affected the total body clearance of tacrolimus only during a limited period after living-donor liver transplantation. The clearance was about 1.35-fold higher in the recipients who had a liver with the CYP3A51 allele than in those with the CYP3A53/3 genotype, whereas bioavailability was ~0.7-fold higher in the recipients who had intestines with the CYP3A51 allele than those with CYP3A5*3/*3. In conclusion, the constructed physiologically-based pharmacokinetic model clarified that the oral clearance of tacrolimus was affected by the CYP3A5 genotypes in both the liver and intestine to the same extent.
在活体肝移植后的成年患者中，术后天数和细胞色素 P450 3A5（CYP3A5）基因型已知会影响他克莫司的药代动力学。在这项研究中，我们构建了一个适应临床数据的基于生理学的药代动力学模型，并评估了肝再生以及肝和肠道 CYP3A5 基因型对他克莫司药代动力学的贡献。结果表明，肝功能立即恢复，仅在活体肝移植后有限的时间内影响他克莫司的全身清除率。具有 CYP3A51 等位基因的肝脏的受者的清除率比具有 CYP3A53/3 基因型的受者高约 1.35 倍，而具有 CYP3A51 等位基因的肠道的受者的生物利用度比具有 CYP3A5*3/*3 的受者高约 0.7 倍。总之，所构建的基于生理学的药代动力学模型阐明了他克莫司的口服清除率受到肝脏和肠道中 CYP3A5 基因型的同等影响。
