Evaluation of Hepatic Disposition of Paroxetine Using Sandwich-Cultured Rat and Human Hepatocytes

Abstract

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 M1-glucuronide, whereas M1-glucuronide and M1-sulfate are found in humans. The primary excretion route of paroxetine-derived radioactivity in rats and humans is bile and urine, respectively. The aim of this study was to examine the usefulness of sandwich-cultured hepatocytes (SCH) to evaluate in vivo species differences of the hepatic disposition of paroxetine between rats and humans. The metabolite profile of [ 3 H]paroxetine in SCH was similar to that in hepatocytes in suspension, and the in vitro metabolite profiles were similar to the published in vivo metabolic pathways for both species. Furthermore, the biliary excretion index (BEI) of formed M1-glucuronide in rat SCH (25.8-50.9%) was higher than that in human SCH (15.1-16.7%). The BEI of formed M1-sulfate (16.4-29.1%) was comparable to that of M1-glucuronide in human SCH, whereas the BEIs of paroxetine were negligible in SCH of both species. Moreover, M1-glucuronide was demonstrated to be a multidrug resistance-associated protein 2 substrate in both species, as determined by its uptake into ATP-binding cassette transporter-expressing membrane vesicles. SCH should prove to be useful to evaluate the processes of hepatic uptake and metabolism of parent drugs and the simultaneous examination of the biliary excretion of both parent drug and liver-derived metabolites.

Recent Progress in Hepatocyte Culture Models and Their Application to the Assessment of Drug Metabolism, Transport, and Toxicity in Drug Discovery: The Value of Tissue Engineering for the Successful Development of a Microphysiological System

“…58 investigated the hepatic disposition of troglitazone using SCH and demonstrated biliary excretion of its sulfate and glucuronide. Matsunaga et al 59 evaluated hepatic disposition of paroxetine in rat and human SCH and showed well-preserved species differences in its hepatic disposition, which includes a series of metabolic steps followed by biliary excretion of metabolites in SCH. In addition, Tetsuka et al 61 investigated a series of events in glucuronidation and biliary excretion of mycophenolic acid (MPA).…”

Glucuronidation and Subsequent Biliary Excretion of Mycophenolic Acid in Rat Sandwich-cultured Hepatocytes

“…15,16) Moreover, there are some reports investigating in vitro biliary excretion of metabolites in addition to the parent compound in SCH. 17,18) Mycophenolic acid (MPA), an inosine 5A-monophosphate dehydrogenase inhibitor, is an immunosuppressive agent to prevent acute rejection in organ transplantation. MPA is frequently administered as a pro-drug (mycophenolic acid mofetil: MMF) that is rapidly converted to MPA in vivo.…”

Optimized Hepatocyte-Like Cells with Functional Drug Transporters Directly-Reprogrammed from Mouse Fibroblasts and their Potential in Drug Disposition and Toxicology

“…One of the most valuable applications of primary hepatocytes is to evaluate drug biliary excretion [4,50]. Here, we determined multiple transporter substrates' hepatobiliary disposition in the optimized iHep cells and compared that with primary hepatocytes.…”