Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Drug Metab Dispos. 2011 Mar;39(3):419-25. doi: 10.1124/dmd.110.035642. Epub 2010 Dec 6.
The aim of this study was to report the effect of diabetes mellitus on the pharmacokinetics of verapamil in a route-dependent manner. Diabetes in rats was induced by streptozotocin. Plasma concentrations of verapamil and its metabolite, norverapamil, were measured after oral (10 mg/kg) or intravenous (1 mg/kg) administration. The concentrations of verapamil in portal plasma after oral administration were also determined. Norverapamil formation was used for assessing CYP3A activity in hepatic and intestinal microsomes of diabetic rats. The protein levels of CYP3A1 and CYP3A2 in liver and intestine were measured by Western blot. It was found that diabetes significantly increased the plasma concentration of verapamil and norverapamil after oral administration, which resulted in a 74% increase in the area under the concentration-time curve (AUC) of verapamil, but the ratio of AUC((norverapamil))/AUC((verapamil)) was significantly decreased by 38%. In contrast, diabetes significantly decreased the AUC of verapamil by 22% after intravenous administration. Diabetes also resulted in increased AUC of verapamil in portal vein by 3.8-fold compared with that in control rats. The absolute bioavailability of verapamil was higher than that of control rats. An in vitro study showed that increased CYP3A activity in the hepatic microsome and decreased CYP3A activity in the intestinal microsome were accompanied by an increase and decrease in the protein expression of CYP3A1/2 in liver and intestine of diabetic rats, respectively. In conclusion, diabetes mellitus revealed a tissue-specific effect on CYP3A activity and expression (induced in liver and inhibited in intestine), resulting in opposite pharmacokinetic behaviors of verapamil after oral and intravenous administration to diabetic rats.
本研究旨在报告糖尿病以依赖于途径的方式对维拉帕米药代动力学的影响。大鼠糖尿病通过链脲佐菌素诱导。口服（10mg/kg）或静脉内（1mg/kg）给予维拉帕米后，测定维拉帕米及其代谢物去甲维拉帕米的血浆浓度。还测定了口服给药后门静脉血浆中的维拉帕米浓度。用糖尿病大鼠肝和肠微粒体中测定去甲维拉帕米的形成来评估 CYP3A 活性。用 Western blot 测定肝和肠中 CYP3A1 和 CYP3A2 的蛋白水平。结果发现，糖尿病显著增加了口服维拉帕米和去甲维拉帕米后的血浆浓度，导致维拉帕米的 AUC 增加了 74%，但 AUC((norverapamil))/AUC((verapamil))的比值却显著降低了 38%。相反，糖尿病显著降低了静脉内给予维拉帕米后的 AUC 减少了 22%。糖尿病还导致与对照大鼠相比门静脉中维拉帕米的 AUC 增加了 3.8 倍。维拉帕米的绝对生物利用度高于对照大鼠。体外研究表明，糖尿病大鼠肝微粒体中 CYP3A 活性增加，肠微粒体中 CYP3A 活性降低，同时肝和肠中 CYP3A1/2 的蛋白表达分别增加和减少。总之，糖尿病对 CYP3A 活性和表达具有组织特异性影响（在肝脏中诱导，在肠道中抑制），导致糖尿病大鼠口服和静脉内给予维拉帕米后的药代动力学行为相反。
