Lee Y H, Lee M H, Shim C K
College of Pharmacy, Seoul National University, Korea.
Pharm Res. 1992 Dec;9(12):1599-606. doi: 10.1023/a:1015868525978.
The effect of uranyl nitrate (UN)-induced acute renal failure (ARF) on the pharmacokinetics of diltiazem (DTZ) was examined in rats through in vitro and in vivo studies. In vitro homogenate studies demonstrated that DTZ was metabolized to deacetyl diltiazem (DAD) predominantly in the liver. Metabolism in the small intestine, kidney, or blood pool was negligible compared with that in the liver. UN-induced ARF (UN-ARF) increased the in vitro hepatic clearance (CLvit) of DTZ 1.4-fold. In vivo pharmacokinetic studies following intravenous (iv) and portal venous (pv) administration revealed that UN-ARF increased the intrinsic clearance (CLi) of DTZ from 243.0 to 414.5 ml/min/kg but decreased its total plasma clearance (CLt) from 90.3 to 64.3 ml/min/kg. The increase in CLi was consistent with the increase in CLvit of the liver. The in vitro plasma free fraction of DTZ (fp) was decreased from 0.25 to 0.14 by UN-ARF, but the in vitro blood/plasma partition of DTZ (Rb) remained constant at unity. From the CLi and fp changes, the plasma intrinsic clearance for unbound DTZ (CLi') was calculated to be increased 2.7-fold, from 1104.5 to 2960.7 ml/min/kg, by UN-ARF. The fp decrease was also reflected in the steady-state distribution volume (Vdss) of DTZ, which was decreased significantly from 3595.5 to 2528.3 ml/kg. The absolute bioavailability of pv DTZ (Fpv) was decreased by UN-ARF from 37.5 to 15.5% but was still much higher than the reported oral bioavailability (6%), indicating poor absorption of DTZ from the GI tract. From the calculation based on a well-stirred pharmacokinetic model, DTZ was found to increase the hepatic blood flow (HBF) of the control rats more than twofold at doses of 3 mg/kg (iv) or 10 mg/kg (pv), possibly due to the vasodilating effect of DTZ. However, the effect of DTZ on HBF was not present in the UN-ARF rats. It is not clear at present whether this could be attributed to vasoconstricting effects of UN-ARF or blockade of the vasodilating effect of DTZ.
通过体外和体内研究，考察了硝酸铀酰（UN）诱导的急性肾衰竭（ARF）对大鼠地尔硫䓬（DTZ）药代动力学的影响。体外匀浆研究表明，DTZ主要在肝脏代谢为去乙酰地尔硫䓬（DAD）。与肝脏相比，小肠、肾脏或血池中的代谢可忽略不计。UN诱导的ARF（UN-ARF）使DTZ的体外肝脏清除率（CLvit）增加了1.4倍。静脉注射（iv）和门静脉注射（pv）后的体内药代动力学研究表明，UN-ARF使DTZ的内在清除率（CLi）从243.0增加至414.5 ml/min/kg，但使其总血浆清除率（CLt）从90.3降至64.3 ml/min/kg。CLi的增加与肝脏CLvit的增加一致。UN-ARF使DTZ的体外血浆游离分数（fp）从0.25降至0.14，但DTZ的体外血/浆分配系数（Rb）保持恒定为1。根据CLi和fp的变化，计算得出UN-ARF使未结合DTZ的血浆内在清除率（CLi'）增加了2.7倍，从1104.5增至2960.7 ml/min/kg。fp的降低也反映在DTZ的稳态分布容积（Vdss）上，Vdss从3595.5显著降至2528.3 ml/kg。pv DTZ的绝对生物利用度（Fpv）因UN-ARF从37.5%降至15.5%，但仍远高于报道的口服生物利用度（6%），表明DTZ从胃肠道的吸收较差。根据一个充分搅拌的药代动力学模型计算发现，在3 mg/kg（iv）或10 mg/kg（pv）剂量下，DTZ使对照大鼠的肝血流量（HBF）增加了两倍多，这可能是由于DTZ的血管舒张作用。然而，DTZ对HBF的影响在UN-ARF大鼠中不存在。目前尚不清楚这是否可归因于UN-ARF的血管收缩作用或DTZ血管舒张作用的阻断。
