Investigation of the effect of rifampicin on drug disposition in the liver and pharmacokinetic modelling

Transporter-mediated pharmacokinetics is one of the determinants in hepatic drug disposition and drug-drug interactions. Among several influx (uptake) transporters expressed in the membranes of hepatocytes, hepatic organic anion-transporting polypeptides (OATPs) are clinically important major transporters to be evaluated during drug development. The aim of this thesis was to investigate the hepatic disposition of pitavastatin in the absence and presence of an OATP/Oatp inhibitor rifampicin using in situ isolated perfused rat liver method with monitoring coproporphyrin I and coproporphyrin III as endogenous biomarkers. The samples were collected from perfusate, liver tissue and bile, and analysed by validated bioanalytical methods. Hepatic and biliary clearances plus hepatic bioavailability of pitavastatin were estimated using model independent analysis. Reasonable correlations between pitavastatin and endogenous biomarkers in the liver and bile were obtained. A mechanistic compartment model composed of perfusate, liver extracellular and intracellular, and bile compartments was developed to simulate hepatobiliary distribution and estimate hepatic uptake and biliary clearances of pitavastatin by simultaneous fitting of the data obtained in two conditions (with and without rifampicin). The current dynamic model, which excludes any extrahepatic variable, delivers a refined clearance estimation to characterize the disposition of pitavastatin in the rat liver.