Hong Soon-Pyo, Chang Kyoung-Sig, Choi Dong-Hyun, Choi Jun-Shik
College of Medicine, Chosun University, Gwangju 501-759, Korea.
Arch Pharm Res. 2007 Jan;30(1):90-5. doi: 10.1007/BF02977783.
The purpose of this study was to investigate the effect of atorvastatin, HMG-CoA reductase inhibitor, on the pharmacokinetics of diltiazem and its active metabolite, desacetyldiltiazem, in rats. Pharmacokinetic parameters of diltiazem and desacetyldiltiazem were determined in rats after oral administration of diltiazem (15 mg x kg(-1)) to rats pretreated with atorvastatin (0.5 or 2.0 mg x kg(-1)). Compared with the control (given diltiazem alone), the pretreatment of atorvastatin significantly altered the pharmacokinetic parameters of diltiazem. The peak concentration (Cmax) and the areas under the plasma concentration-time curve (AUC) of diltiazem were significantly (p < 0.05, 0.5 mg x kg(-1); p < 0.01, 2.0 mg x kg(-1)) increased in the presence of atorvastatin. The AUC of diltiazem was increased by 1.40-fold in rats pretreated with 0.5 mg x kg(-1) atorvastatin, and 1.77-fold in rats pretreated with 2.0 mg x kg(-1) atorvastatin. Consequently, absolute bioavailability values of diltiazem pretreated with atorvastatin (8.4-10.6%)were significantly higher (p < 0.05) than that in the control group (6.6%). Although the pretreatment of atorvastatin significantly (p < 0.05) increased the AUC of desacetyldiltiazem, metabolite-parent AUC ratio (M.R.) in the presence of atorvastatin (0.5 or 2.0 mg x kg(-1)) was significantly decreased compared to the control group, implying that atorvastatin could be effective to inhibit the metabolism of diltiazem. In conclusion, the concomitant use of atorvastatin significantly enhanced the oral exposure of diltiazem in rats.
本研究的目的是探讨HMG-CoA还原酶抑制剂阿托伐他汀对大鼠体内地尔硫䓬及其活性代谢物去乙酰基地尔硫䓬药代动力学的影响。在给用阿托伐他汀（0.5或2.0mg·kg⁻¹）预处理的大鼠口服地尔硫䓬（15mg·kg⁻¹）后，测定大鼠体内地尔硫䓬和去乙酰基地尔硫䓬的药代动力学参数。与对照组（单独给予地尔硫䓬）相比，阿托伐他汀预处理显著改变了地尔硫䓬的药代动力学参数。在阿托伐他汀存在的情况下，地尔硫䓬的峰浓度（Cmax）和血浆浓度-时间曲线下面积（AUC）显著增加（0.5mg·kg⁻¹时，p<0.05；2.0mg·kg⁻¹时，p<0.01）。在用0.5mg·kg⁻¹阿托伐他汀预处理的大鼠中，地尔硫䓬的AUC增加了1.40倍，在用2.0mg·kg⁻¹阿托伐他汀预处理的大鼠中增加了1.77倍。因此，用阿托伐他汀预处理的地尔硫䓬的绝对生物利用度值（8.4-10.6%）显著高于对照组（6.6%）（p<0.05）。虽然阿托伐他汀预处理显著增加了去乙酰基地尔硫䓬的AUC（p<0.05），但与对照组相比，在阿托伐他汀（0.5或2.0mg·kg⁻¹）存在的情况下，代谢物-母体AUC比值（M.R.）显著降低，这意味着阿托伐他汀可有效抑制地尔硫䓬的代谢。总之，阿托伐他汀与地尔硫䓬同时使用可显著增强大鼠体内地尔硫䓬的口服暴露量。
