半胱氨酸对蛋白质 - 热量营养不良大鼠二甲双胍药代动力学的影响：部分参数恢复至对照水平。

Effects of cysteine on metformin pharmacokinetics in rats with protein-calorie malnutrition: partial restoration of some parameters to control levels.

作者信息

Choi Young H, Lee Inchul, Lee Myung G

机构信息

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1, Shinlim-Dong, Kwanak-Gu, Seoul 151-742, South Korea.

出版信息

J Pharm Pharmacol. 2008 Feb;60(2):153-61. doi: 10.1211/jpp.60.2.0003.

DOI:10.1211/jpp.60.2.0003

PMID:18237462

Abstract

Metformin is metabolized primarily via hepatic microsomal cytochrome P450 (CYP)2C11, CYP2D1 and CYP3A1/2 in rats. The expression and mRNA levels of hepatic CYP2C11 and CYP3A1/2 are decreased in rats with protein-calorie malnutrition (PCM), but these levels are fully or partially restored to control levels in PMC rats by oral cysteine supplementation (PCMC rats). Thus, it would be expected that the pharmacokinetic parameters of metformin in PCM rats would be returned to control levels in PCMC rats. Metformin was administered i.v. (100 mg kg(-1)) and orally (100 mg kg(-1)) to control, CC (control rats with oral cysteine supplementation), PCM and PCMC rats. The following pharmacokinetic parameters of metformin following i.v. administration were restored from levels in PCM rats to levels in control rats in PCMC rats: intrinsic clearance (0.0350, 0.0309, 0.0253 and 0.0316 mL min(-1) mg(-1) protein for control, CC, PCM, and PCMC rats, respectively), total area under the plasma concentration-time curve from time zero to time infinity (AUC; 4110, 4290, 5540 and 4430 microg min mL(-1), respectively), and time-averaged non-renal clearance (8.12, 7.95, 5.94 and 8.17 mL min(-1) kg(-1), respectively). AUC values following oral administration were comparable between control and PCMC rats (1520, 1480, 2290 and 1680 microg min mL(-1), respectively).

摘要

二甲双胍在大鼠体内主要通过肝脏微粒体细胞色素P450（CYP）2C11、CYP2D1和CYP3A1/2进行代谢。蛋白质 - 热量营养不良（PCM）大鼠肝脏中CYP2C11和CYP3A1/2的表达及mRNA水平降低，但通过口服半胱氨酸补充（PCMC大鼠）后，这些水平在PCM大鼠中可完全或部分恢复至对照水平。因此，可以预期二甲双胍在PCM大鼠中的药代动力学参数在PCMC大鼠中会恢复至对照水平。分别对对照、CC（口服半胱氨酸补充的对照大鼠）、PCM和PCMC大鼠静脉注射（100 mg kg⁻¹）和口服（100 mg kg⁻¹）二甲双胍。静脉注射后二甲双胍的以下药代动力学参数在PCMC大鼠中从PCM大鼠的水平恢复至对照大鼠的水平：内在清除率（对照、CC、PCM和PCMC大鼠分别为0.0350、0.0309、0.0253和0.0316 mL min⁻¹ mg⁻¹蛋白质）、从时间零至无穷大的血浆浓度 - 时间曲线下的总面积（AUC；分别为4110、4290、5540和4430 μg min mL⁻¹）以及时间平均非肾清除率（分别为8.12、7.95、5.94和8.17 mL min⁻¹ kg⁻¹）。对照和PCMC大鼠口服给药后的AUC值相当（分别为1520、1480、2290和1680 μg min mL⁻¹）。