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首页> 外文期刊>Journal of pharmacokinetics and biopharmaceutics >Pharmacokinetic and pharmacodynamic evaluation for tissue-selective inhibition of cholesterol synthesis by pravastatin.
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Pharmacokinetic and pharmacodynamic evaluation for tissue-selective inhibition of cholesterol synthesis by pravastatin.

机译：普伐他汀对胆固醇合成的组织选择性抑制的药代动力学和药效学评价。

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摘要

The tissue-selective inhibition of cholesterol synthesis by pravastatin was evaluated pharmacokinetically and pharmacodynamically. Plasma, tissue, urine, and bile concentrations were measured after i.v. bolus injection of pravastatin to rats at various doses. The total body clearance and steady state volume of distribution decreased with increasing dose. A saturable biliary excretion was also observed. The time course of plasma and liver concentrations was described by a three-compartment model, consisting of a central compartment, a deep compartment with an nonsaturable uptake process, and a shallow compartment with saturable uptake and nonsaturable elimination processes. It suggests that a mechanism for the decrease in the total body clearance and distribution volume might be explained by a saturation of pravastatin uptake into the liver. Plasma concentration data after oral administration was also fitted to the same model by connecting an absorption compartment to the shallow compartment. The inhibitory activity of pravastatin against cholesterol synthesis in liver could be related to the concentration in the shallow compartment via a sigmoidal Emax model and the obtained pharmacodynamic parameters were comparable to those in vitro. Results suggest that the carrier-mediated hepatic uptake of pravastatin is actually responsible for the hepatoselective inhibition of cholesterol synthesis under physiological conditions.
机译：通过药代动力学和药效学评估了普伐他汀对胆固醇合成的组织选择性抑制。静脉注射后测量血浆，组织，尿液和胆汁浓度。以不同剂量向大鼠推注普伐他汀。总体体内清除率和稳态分布体积随剂量增加而降低。还观察到饱和胆汁排泄。血浆和肝脏浓度的时间过程由三室模型描述，该模型由中央室，具有不饱和吸收过程的深室和具有饱和吸收和不饱和消除过程的浅室组成。这表明总体清除率和分布体积减少的机制可能是由于普伐他汀对肝脏的摄取饱和所致。通过将吸收室连接至浅室，口服给药后的血浆浓度数据也适用于同一模型。普伐他汀对肝脏胆固醇合成的抑制活性可能与乙状结肠Emax模型有关，且与浅室的浓度有关，所获得的药效学参数与体外相当。结果表明，在生理条件下，肝素对普伐他汀的载体介导的摄取实际上是肝脏选择性抑制胆固醇合成的原因。

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