title: Metabolic stability and uptake by human hepatocytes of pitavastatin, a new inhibitor of HMG-CoA reductase.
abstract: To gain a better understanding of the metabolic stability and transport of pitavastatin (CAS 147526-32-7), a new and potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, experiments were conducted using human hepatocytes and oocytes of Xenopus laevis expressing human organic anion transporting polypeptide-2 (OATP2), respectively. Almost the entire radioactivity was from the unchanged substance or lactone form in human hepatocytes, and the cytochrome P450 (CYP)-mediated metabolism of pitavastatin was negligible. The results suggested that CYPs are not critically involved in determining the metabolic fate of pitavastatin. The hepatic uptake of pitavastatin reached saturation with a Km of 2.99 +/- 0.79 micromol/L. Also, the uptake of pitavastatin was mediated by OATP2 expressed in oocytes with a Km of 5.53 +/- 1.70 micromol/L. These results indicated that OATP2 plays a major role in the distribution of pitavastatin in liver. Furthermore, to elucidate the increase in the plasma concentration of pitavastatin in a clinical setting, the inhibitory effect of ciclosporin (cyclosporin A, CAS 59865-13-3) on the uptake of pitavastatin was examined. The uptake of pitavastatin was inhibited in the presence of cyclosporin A and the apparent IC50 value was 2.91 +/- 0.78 micromol/L. This result may at least partly explain the drug-drug interaction between pitavastatin and cyclosporin A. In conclusion, the characterization of transporters needs to be taken into account to avoid transporter-mediated drug-drug interaction.
authors.affiliation: Tokyo New Drug Research Laboratories I, Kowa Company Ltd, Tokyo, Japan. h-fujino@kowa.co.jp
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujino
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nakai
authors.forename: Rie
authors.initials: R
authors.lastname: Nakagomi
authors.forename: Motoko
authors.initials: M
authors.lastname: Saito
authors.forename: Taro
authors.initials: T
authors.lastname: Tokui
authors.forename: Junji
authors.initials: J
authors.lastname: Kojima
mesh_terms: D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D015925:Cryopreservation; D016572:Cyclosporine / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics*; D007202:Indicators and Reagents; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1 / Q000378:metabolism; D011804:Quinolines / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D014982:Xenopus laevis
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007202:Indicators and Reagents; D027381:Liver-Specific Organic Anion Transporter 1; D011804:Quinolines; D004958:Estradiol; D016572:Cyclosporine; C108475:pitavastatin