Ahn Choong Y, Kim Eun J, Kwon Jong W, Chung Suk J, Kim Sang G, Shim Chang-K, Lee Myung G
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 151-742 Seoul, South Korea.
Life Sci. 2003 Aug 22;73(14):1783-94. doi: 10.1016/s0024-3205(03)00540-x.
Effects of cysteine on the pharmacokinetics of clarithromycin were investigated after intravenous administration of the drug at a dose of 20 mg/kg to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutrition, 4-week fed on 5% casein diet) and PCMC (PCM treated with 250 mg/kg for oral cysteine twice daily during the fourth week). Clarithromycin has been reported to be metabolized via hepatic microsomal cytochrome P450 (CYP) 3A4 to 14-hydroxyclarithromycin (primary metabolite of clarithromycin) in human subjects. It has also been reported that in rats with PCM, CYP3A23 level decreased to 40-50% of control level, but decreased CYP3A23 level in rats with PCM completely returned to control level by oral cysteine supplementation (rats with PCMC). Human CYP3A4 and rat CYP3A23 proteins have 73% homology. In rats with PCM, the area under the plasma concentration-time curve from time zero to time infinity, AUC (567, 853 and 558 microg min/ml for control rats and rats with PCM and PCMC, respectively) and percentage of clarithromycin remaining after incubation with liver homogenate (69.6, 83.9 and 71.7%) were significantly greater than those in control rats and rats with PCMC. Moreover, in rats with PCM, the total body clearance, CL (35.3, 23.4 and 35.8 ml/min/kg), nonrenal clearance, CL(NR) (21.3, 15.2 and 24.1 ml/min/kg) and maximum velocity for the disappearance of clarithromycin after incubation with hepatic microsomal fraction, V(max) (351, 211 and 372 pmol/min/mg protein) were significantly slower than those in control rats and rats with PCMC. However, above mentioned each parameter was not significantly different between control rats and rats with PCMC. The above data suggested that metabolism of clarithromycin decreased significantly in rats with PCM as compared to control due to significantly decreased level of CYP3A23 in the rats. By cysteine supplementation (rats with PCMC), some pharmacokinetic parameters of clarithromycin (AUC, CL, CL(NR) and V(max)) were restored fully to control levels because CYP3A23 level was completely returned to control level in rats with PCMC.
在以20mg/kg的剂量向对照大鼠（喂食23%酪蛋白饮食4周）、蛋白质 - 热量营养不良大鼠（PCM，喂食5%酪蛋白饮食4周）和PCMC大鼠（第四周期间每天两次口服250mg/kg半胱氨酸治疗的PCM大鼠）静脉注射克拉霉素后，研究了半胱氨酸对克拉霉素药代动力学的影响。据报道，在人类受试者中，克拉霉素通过肝脏微粒体细胞色素P450（CYP）3A4代谢为14 - 羟基克拉霉素（克拉霉素的主要代谢产物）。也有报道称，在PCM大鼠中，CYP3A23水平降至对照水平的40 - 50%，但通过口服补充半胱氨酸（PCMC大鼠），PCM大鼠中降低的CYP3A23水平完全恢复到对照水平。人类CYP3A4和大鼠CYP3A23蛋白具有73%的同源性。在PCM大鼠中，从时间零到时间无穷大的血浆浓度 - 时间曲线下面积，AUC（对照大鼠、PCM大鼠和PCMC大鼠分别为567、853和558μg·min/ml）以及与肝匀浆孵育后克拉霉素剩余百分比（69.6、83.9和71.7%）均显著高于对照大鼠和PCMC大鼠。此外，在PCM大鼠中，总体清除率，CL（35.3、23.4和35.8ml/min/kg）、非肾清除率，CL(NR)（21.3、15.2和24.1ml/min/kg）以及与肝微粒体部分孵育后克拉霉素消失的最大速度，V(max)（351、211和372pmol/min/mg蛋白）均显著慢于对照大鼠和PCMC大鼠。然而，对照大鼠和PCMC大鼠之间上述各参数无显著差异。上述数据表明，与对照相比，PCM大鼠中克拉霉素的代谢显著降低，原因是大鼠中CYP3A23水平显著降低。通过补充半胱氨酸（PCMC大鼠），克拉霉素的一些药代动力学参数（AUC、CL、CL(NR)和V(max)）完全恢复到对照水平，因为PCMC大鼠中CYP3A23水平完全恢复到对照水平。
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