Pitavastatin is a more sensitive and selective organic anion‐transporting polypeptide 1B clinical probe than rosuvastatin. (September 2014)

• Record Type: Journal Article
• Authors: Prueksaritanont, Thomayant; Chu, Xiaoyan; Evers, Raymond; Klopfer, Stephanie O.; Caro, Luzelena; Kothare, Prajakti A.; Dempsey, Cynthia; Rasmussen, Scott; Houle, Robert; Chan, Grace; Cai, Xiaoxin; Valesky, Robert; Fraser, Iain P.; Stoch, S. Aubrey
• Is Part Of: British journal of clinical pharmacology. Volume 78:Number 3(2014:Sep.)
• Page Start: 587
• Page End: 598
• Publication Date: 2014-09
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12377
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12377-sec-0001" sec-type="section"> <title>Aims</title> <p>Rosuvastatin and pitavastatin have been proposed as probe substrates for the organic anion‐transporting polypeptide (OATP) 1B, but clinical data on their relative sensitivity and selectivity to OATP1B inhibitors are lacking. A clinical study was therefore conducted to determine their relative suitability as OATP1B probes using single oral (PO) and intravenous (IV) doses of the OATP1B inhibitor rifampicin, accompanied by a comprehensive <italic>in vitro</italic> assessment of rifampicin inhibitory potential on statin transporters.</p> </sec> <sec id="bcp12377-sec-0002" sec-type="section"> <title>Methods</title> <p>The clinical study comprised of two separate panels of eight healthy subjects. In each panel, subjects were randomized to receive a single oral dose of rosuvastatin (5 mg) or pitavastatin (1 mg) administered alone, concomitantly with rifampicin (600 mg) PO or IV. The <italic>in vitro</italic> transporter studies were performed using hepatocytes and recombinant expression systems.</p> </sec> <sec id="bcp12377-sec-0003" sec-type="section"> <title>Results</title> <p>Rifampicin markedly increased exposures of both statins, with greater differential increases after PO <italic>vs.</italic> IV rifampicin only for rosuvastatin. The magnitudes of the increases in area under the plasma concentration–time curve were 5.7‐ and 7.6‐fold for pitavastatin and 4.4‐ and 3.3‐fold for rosuvastatin, after PO and IV rifampicin, respectively. <italic>In vitro</italic> studies showed that rifampicin was an inhibitor of OATP1B1 and OATP1B3, breast cancer resistance protein and multidrug resistance protein 2, but not of organic anion transporter 3.</p> </sec> <sec id="bcp12377-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The results indicate that pitavastatin is a more sensitive and selective and thus preferred clinical OATP1B probe substrate than rosuvastatin, and that a single IV dose of rifampicin is a more selective OATP1B inhibitor than a PO dose.</p> </sec> </abstract>