title: Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase--effect of cMOAT deficiency on hepatobiliary excretion in rats and of mdr1a/b gene disruption on tissue distribution in mice.
abstract: Pitavastatin is a potent competitive inhibitor of HMG-CoA reductase. In the current study, to elucidate the hepatobiliary excretion of pitavastatin, we investigated the plasma concentration and biliary excretion of (14)C-pitavastatin in EHBR. We also evaluated the distribution of pitavastatin in mdr1a/b knockout mice by whole body autoradiography and quantitative radioassay. In view of the widespread clinical use of pitavastatin and the importance of drug-drug interaction, the inhibitory effect on Pgp-mediated activation of ATPase was also investigated. No marked difference was observed in the plasma concentration and biliary excretion of radioactivity between SDR and EHBR after dosing of (14)C-pitavastatin. Little radioactive transfer into the brain was detected in mdr1a/b knockout mice and the ATPase activity of human Pgp was negligible in the presence of pitavastatin. Moreover, no inhibitory effect on the Pgp-mediated activation of ATPase by verapamil was found in the presence of pitavastatin over a wide concentration range. These results indicated that a cMOAT and Pgp-mediated transport mechanism did not play a major role in the distribution of pitavastatin.
authors.affiliation: Tokyo New Drug Research Laboratories I, Kowa Company Ltd., Higashimurayama, Tokyo, Japan. h-fujino@kowa.co.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujino
authors.forename: Iwao
authors.initials: I
authors.lastname: Yamada
authors.forename: Syunsuke
authors.initials: S
authors.lastname: Shimada
authors.forename: Junji
authors.initials: J
authors.lastname: Kojima