Transporter-mediated influx and efflux mechanisms of pitavastatin, a new inhibitor of HMG-CoA reductase.
The purpose of this study was to gain a better understanding of the transport mechanism of pitavastatin, a novel synthetic HMG-CoA reductase inhibitor. Experiments were performed using oocytes of Xenopus laevis expressing several solute carrier (SLC) transporters and recombinant membrane vesicles expressing several human ABC transporters. The acid form of pitavastatin was shown to be a substrate for human OATP1, OATP2, OATP8, OAT3 and NTCP, and for rat Oatp1 and Oatp4 with relatively low K(m) values. In contrast, these SLC transporters were not involved in the uptake of the lactone form. A significant stimulatory effect was exhibited by pitavastatin lactone, while the acid form did not exhibit ATPase hydrolysis of P-glycoprotein. In the case of breast cancer resistant protein (BCRP), the acid form of pitavastatin is a substrate, whereas the lactone form is not. Taking these results into consideration, several SLC and ABC transporters were identified as critical to the distribution and excretion of pitavastatin in the body. This study showed, for the first time, that acid and lactone forms of pitavastatin differ in substrate activity towards uptake and efflux transporters. These results will potentially contribute to the differences in the pharmacokinetic profiles of pitavastatin.
Fujino
Hideki
H
Tokyo New Drug Research Laboratories I, Kowa Company Ltd, 2-17-43 Noguchicho, Higashimurayama, Tokyo 189-0022, Japan. h-fujino@kowa.co.jp
Saito
Tsuyoshi
T
Ogawa
Shin-Ichiro
S
Kojima
Junji
J
D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis
C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D002250:Carbon Radioisotopes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D009363:Neoplasm Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D011804:Quinolines; C421209:SLCO1B3 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D027981:Symporters; C071908:sodium-bile acid cotransporter; D000251:Adenosine Triphosphatases; C108475:pitavastatin