Tian Hui, Ou Junhai, Strom Stephen C, Venkataramanan Raman
718 Salk Hall, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA. rv+@pitt.edu
Drug Metab Dispos. 2005 Mar;33(3):329-35. doi: 10.1124/dmd.104.002287. Epub 2004 Nov 2.
Hepatic regeneration is very critical to the success of living donor liver transplantation, which allows a reduced size liver to grow in size to accommodate the requirements of both the donor and the recipient. The objectives of this study were to evaluate 1) the hepatic metabolism of the two immunosuppressive drugs, tacrolimus and mycophenolic acid (MPA), and 2) the pharmacokinetics of tacrolimus and mycophenolic acid at various time points after initiation of hepatic regeneration by partial hepatectomy in rats. The hepatic intrinsic clearance of tacrolimus was decreased to 70% and 51% of the control level at the 24th h and the 6th day, respectively, but returned to normal level by day 14. The total body clearance of tacrolimus was reduced transiently but recovered completely by day 18. The hepatic intrinsic clearance of MPA was decreased to 52% and 51% of that in control rats at the 24th h and the 6th day, respectively, but recovered to normal level by day 14. The total body clearance of MPA was reduced at the 24th h but recovered by day 6. The magnitude of reduction in the clearance of tacrolimus and MPA was much smaller than what was predicted from in vitro data. The elimination clearance of MPA glucuronide was also impaired during hepatic regeneration but recovered to normal level with time. In conclusion, the pharmacokinetics of tacrolimus and mycophenolic acid were altered during hepatic regeneration but recovered completely at different rates over time. Caution must be exercised in extrapolating in vitro data to in vivo conditions during hepatic regeneration.
肝再生对于活体供肝肝移植的成功至关重要，它能使缩小体积的肝脏增大，以满足供体和受体双方的需求。本研究的目的是评估：1）两种免疫抑制药物他克莫司和霉酚酸（MPA）的肝脏代谢；2）大鼠部分肝切除启动肝再生后不同时间点他克莫司和霉酚酸的药代动力学。他克莫司的肝脏内在清除率在第24小时和第6天时分别降至对照水平的70%和51%，但在第14天时恢复到正常水平。他克莫司的总体清除率短暂降低，但在第18天时完全恢复。MPA的肝脏内在清除率在第24小时和第6天时分别降至对照大鼠的52%和51%，但在第14天时恢复到正常水平。MPA的总体清除率在第24小时降低，但在第6天时恢复。他克莫司和MPA清除率降低的幅度远小于体外数据预测的幅度。MPA葡糖醛酸的消除清除率在肝再生期间也受损，但随时间恢复到正常水平。总之，他克莫司和霉酚酸的药代动力学在肝再生期间发生改变，但随时间以不同速率完全恢复。在肝再生期间将体外数据外推至体内情况时必须谨慎。
