Evaluation of hepatic disposition of paroxetine using sandwich-cultured rat and human hepatocytes.

DMD # 49817 1 Evaluation of hepatic disposition of paroxetine using sandwich - cultured rat and human hepatocytes

Dmd049817 735..743

Paroxetine, a selective serotonin reuptake inhibitor, is metabolized in the liver and excreted into bile and urine as metabolites, but species differences have been observed in hepatic disposition between rats and humans. A major metabolite in rats is M1glucuronide, whereas M1-glucuronide and M1-sulfate are found in humans. The primary excretion route of paroxetine-derived radioactivity in rats...

Development of a novel in vitro model to predict hepatic clearance using fresh, cryopreserved, and sandwich-cultured hepatocytes.

Sixty-four compounds with diverse structures were used in evaluation of intrinsic clearance by various hepatocyte preparations from rats, dogs, monkeys, and humans. Intrinsic clearance (CL(int)) was calculated from the ratio of the initial amount of the test compound minus the amount remaining after 2 h of incubation and the corresponding area under the concentration versus time curve. The pred...

Assessment of drug interactions in hepatobiliary transport using rhodamine 123 in sandwich-cultured rat hepatocytes.

The purpose of the present study was to explore the utility of sandwich-cultured rat hepatocytes as an in vitro tool to examine drug interactions at the hepatic transport level. Rhodamine 123 was used as a model substrate for P-glycoprotein-mediated biliary excretion. Effects of various types of P-glycoprotein modulation on the biliary excretion index (BEI; a relative measure of the extent of b...

Culture period-dependent changes in the uptake of transporter substrates in sandwich-cultured rat and human hepatocytes.

Sandwich-cultured hepatocytes (SCH) are a useful tool for evaluating hepatobiliary drug transport in vitro. Some studies have investigated the in vitro-in vivo correlations of the biliary clearance of drugs using SCH. In most cases, the biliary clearance observed in vivo correlated well with the predicted clearance, but the predicted absolute values were underestimated when based on in vitro ex...