This study was designed to develop a physiologically-based pharmacokinetic/pharmacodynamic model for drugs whose pharmacokinetics are influenced by their dose-dependent pharmacological effects. Since blood flow rate is one of the important factors that determine the distribution and elimination processes of drugs, we used inaperisone [IPS, (±)-4'-ethyl-2-methyl-3-(1-pyrrolidinyl)-propiophenone hydrochloride], a novel centrally acting muscle relaxant that has been found by us to significantly alter muscle and fat blood flow rates in a dose-dependent manner, as a model compound. With regard to the changes in muscle blood flow rate exhibited by IPS, the brain was shown to be the major site of action based on changes in the observed blood flow rates, determined by the 51Cr-labeled microsphere method, in rats injected iv and intracerebroventricularly with various doses of IPS. Consequently, the blood flow rates in the muscle and fat were well correlated with the concentration of IPS in the brain using Hill's equation. Moreover, hepatic and renal intrinsic clearance of IPS at steady-state were determined by the constant iv infusion method. The saturation of in vivo hepatic and renal metabolisms of IPS was found at venous plasma concentrations higher than 1 μg/ml. Taken all together, we developed a physiologically-based pharmacokinetic model of IPS combined with its pharmacological effect in rats, which could simulate the concentration-dependent changes in blood flow rates based on the drug concentrations at the site of action. The predicted serum and tissue concentrations of IPS after iv dosage of 5 mg/kg were in agreement with the observed concentrations, and a goodness of fit was considerably improved in the muscle as compared with a conventional physiological model, which assumes that tissue blood flow rates are normal and constant. Moreover, our model could predict the nonlinear bioavailability of IPS observed after intraportal administration at various doses.
|Number of pages||9|
|Journal||Drug Metabolism and Disposition|
|Publication status||Published - 1990|
ASJC Scopus subject areas
- Pharmaceutical Science