Open AccessSpecies differences in sinusoidal and canalicular efflux transport of mycophenolic acid 7‐ O‐ glucuronide in sandwich‐cultured hepatocytes
Author(s) -
Tetsuka Kazuhiro,
Gerst Nicolas,
Tamura Kouichi,
Masters Jeffrey N.
Publication year - 2014
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.35
Subject(s) - efflux , mycophenolic acid , glucuronide , chemistry , chromatography , pharmacology , biochemistry , medicine , metabolism , transplantation
Metabolism and sinusoidal/canalicular efflux of mycophenolic acid ( MPA ) was investigated using sandwich‐cultured hepatocytes ( SCH s). After applying MPA to SCH s from humans, wild‐type rats, and multidrug resistance‐associated protein (Mrp) 2‐deficient rats, the MPA metabolites 7‐ O‐ glucuronide ( MPAG ) and acyl glucuronide (Ac MPAG ) were detected in the intracellular compartment of the SCH s. Sinusoidal efflux of MPAG was detected in all SCH preparations including Mrp2‐deficient rat SCH s, whereas canalicular efflux of MPAG was observed in wild‐type rat and human SCH s but not in Mrp2‐deficient rat SCH s. The ratio of canalicular efflux to net (canalicular plus sinusoidal) efflux was 37 ± 8% in wild‐type rat SCH s, while the ratio in human SCH s was significantly lower (20 ± 2%, P < 0.05), indicating species differences in the direction of hepatic MPAG transport. This 20% ratio in human SCH s corresponds to a high sinusoidal MPAG efflux (80%) that can in part account for the urine‐dominated recovery of MPAG in humans. Both sinusoidal and canalicular MPAG efflux in rat SCH s shows a good correspondence to urinary and biliary recovery of MPAG after MPA dosing. The sinusoidal efflux of Ac MPAG in human SCH s was detected from one out of three donors, suggesting donor‐to‐donor variation. In conclusion, this study demonstrates the predictive value of SCH s for elucidating the interplay of metabolism and efflux transport, in addition to demonstrating a species difference between rat and human in sinusoidal and canalicular efflux of MPAG .