Suh J H, Kang H E, Yoon I S, Yang S H, Kim S H, Lee H J, Shim C-K, Lee M G
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
Xenobiotica. 2011 Oct;41(10):885-94. doi: 10.3109/00498254.2011.585186. Epub 2011 May 31.
Protein-calorie malnutrition (PCM) occurs frequently in advanced cancer patients and has a profound impact on the toxicity of many drugs. Thus, the pharmacokinetics of etoposide were evaluated in control, control with cysteine (CC), PCM, and PCM with cysteine (PCMC) rats. Etoposide was administered intravenously (2 mg/kg) or orally (10 mg/kg). Changes in hepatic and intestinal cytochrome P450s (CYPs) and effects of cysteine on intestinal P-glycoprotein (P-gp)-mediated efflux were also measured. In PCM rats, the CL(NR) (AUC(0-∞)) of intravenous etoposide was significantly slower (greater) than that in controls, because of the significant decrease in the hepatic CYP3A subfamily and P-gp. In PCMC rats, the slowed CL(NR) of etoposide in PCM rats was restored to the control level by cysteine treatment. PCMC rats showed a significantly greater AUC(0-6 h) of oral etoposide than PCM rats, primarily because of the increased gastrointestinal absorption of etoposide as a result of the inhibition of intestinal P-gp by cysteine. The gastrointestinal absorption of an oral anticancer drug, which is a substrate of P-gp, may be improved by co-administration of cysteine in advanced cancer patients if the present rat data can be extrapolated to patients.
蛋白质 - 热量营养不良（PCM）在晚期癌症患者中频繁发生，并且对许多药物的毒性有深远影响。因此，在对照大鼠、半胱氨酸对照（CC）大鼠、PCM大鼠和半胱氨酸PCM（PCMC）大鼠中评估了依托泊苷的药代动力学。依托泊苷通过静脉注射（2mg/kg）或口服（10mg/kg）给药。还测量了肝脏和肠道细胞色素P450（CYPs）的变化以及半胱氨酸对肠道P-糖蛋白（P-gp）介导的外排的影响。在PCM大鼠中，静脉注射依托泊苷的CL（NR）（AUC（0-∞））明显慢于（大于）对照大鼠，这是由于肝脏CYP3A亚家族和P-gp显著减少。在PCMC大鼠中，PCM大鼠中依托泊苷减慢的CL（NR）通过半胱氨酸治疗恢复到对照水平。PCMC大鼠口服依托泊苷的AUC（0-6h）比PCM大鼠显著更大，这主要是由于半胱氨酸抑制肠道P-gp导致依托泊苷的胃肠道吸收增加。如果目前大鼠的数据能够外推至患者，那么在晚期癌症患者中联合使用半胱氨酸可能会改善作为P-gp底物的口服抗癌药物的胃肠道吸收。
