四氧嘧啶或链脲佐菌素诱导糖尿病大鼠的药物药代动力学：与 I 型糖尿病患者的比较。
Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus.
机构信息
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
出版信息
J Pharm Pharmacol. 2010 Jan;62(1):1-23. doi: 10.1211/jpp.62.01.0001.
OBJECTIVES
In rats with diabetes mellitus induced by alloxan (DMIA) or streptozocin (DMIS), changes in the cytochrome P450 (CYP) isozymes in the liver, lung, kidney, intestine, brain, and testis have been reported based on Western blot analysis, Northern blot analysis, and various enzyme activities. Changes in phase II enzyme activities have been reported also. Hence, in this review, changes in the pharmacokinetics of drugs that were mainly conjugated and metabolized via CYPs or phase II isozymes in rats with DMIA or DMIS, as reported in various literature, have been explained. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized in the kidney, and that were excreted mainly via the kidney or bile in DMIA or DMIS rats were reviewed also. For drugs mainly metabolized via hepatic CYP isozymes, the changes in the total area under the plasma concentration-time curve from time zero to time infinity (AUC) of metabolites, AUC(metabolite)/AUC(parent drug) ratios, or the time-averaged nonrenal and total body clearances (CL(NR) and CL, respectively) of parent drugs as reported in the literature have been compared.
KEY FINDINGS
After intravenous administration of drugs that were mainly metabolized via hepatic CYP isozymes, their hepatic clearances were found to be dependent on the in-vitro hepatic intrinsic clearance (CL(int)) for the disappearance of the parent drug (or in the formation of the metabolite), the free fractions of the drugs in the plasma, or the hepatic blood flow rate depending on their hepatic extraction ratios. The changes in the pharmacokinetics of drugs that were mainly conjugated and mainly metabolized via the kidney in DMIA or DMIS rats were dependent on the drugs. However, the biliary or renal CL values of drugs that were mainly excreted via the kidney or bile in DMIA or DMIS rats were faster.
SUMMARY
Pharmacokinetic studies of drugs in patients with type I diabetes mellitus were scarce. Moreover, similar and different results for drug pharmacokinetics were obtained between diabetic rats and patients with type I diabetes mellitus. Thus, present experimental rat data should be extrapolated carefully in humans.
目的
在由别嘌呤醇（DMIA）或链脲佐菌素（DMIS）诱导的糖尿病大鼠中，据报道通过 Western blot 分析、Northern blot 分析和各种酶活性，肝、肺、肾、肠、脑和睾丸中的细胞色素 P450（CYP）同工酶发生变化。也有报道称二期酶活性发生变化。因此，在这篇综述中，主要通过 CYP 同工酶或二期同工酶结合和代谢的药物在 DMIA 或 DMIS 大鼠中的药代动力学变化，根据各种文献进行了解释。还综述了在 DMIA 或 DMIS 大鼠中主要通过肾脏结合和代谢，主要通过肾脏或胆汁排泄的药物的药代动力学变化。对于主要通过肝 CYP 同工酶代谢的药物，文献中报道了代谢物的零时间至无穷时间（AUC）的总曲线下面积（AUC）、代谢物 AUC/母药 AUC 比值或母体药物的平均非肾和总清除率（CLNR 和 CL，分别）的变化进行了比较。
主要发现
静脉给予主要通过肝 CYP 同工酶代谢的药物后，发现其肝清除率取决于体外肝内在清除率（CL(int)），用于消失的母体药物（或形成的代谢物）、药物在血浆中的游离分数或肝血流率，这取决于它们的肝提取率。在 DMIA 或 DMIS 大鼠中主要通过肾脏结合和代谢的药物的药代动力学变化取决于药物本身。然而，DMIA 或 DMIS 大鼠中主要通过肾脏或胆汁排泄的药物的胆汁或肾清除率更快。
总结
I 型糖尿病患者的药物药代动力学研究很少。此外，糖尿病大鼠和 I 型糖尿病患者的药物药代动力学结果既有相似之处，也有不同之处。因此，目前的实验大鼠数据在人体中需要谨慎推断。
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