Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin

Abstract

Pitavastatin, a novel potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is distributed selectively to the liver and excreted into bile in unchanged form in rats. We reported previously that the hepatic uptake is mainly mediated by organic anion transporting polypeptide (OATP) 1B1, whereas the biliary excretion mechanism remains to be clarified. In the present study, we investigated the role of breast cancer resistance protein (BCRP) in the biliary excretion of pitavastatin. The ATP-dependent uptake of pitavastatin by human and mouse BCRP-expressing membrane vesicles was significantly higher compared with that by control vesicles with K m values of 5.73 and 4.77 M, respectively. The biliary excretion clearance of pitavastatin in Bcrp1(Ϫ/Ϫ) mice was decreased to one-tenth of that in control mice. The biliary excretion of pitavastatin was unchanged between control and Eisai hyperbilirubinemic rats, indicating a minor contribution of multidrug resistance-associated protein (Mrp) 2. This observation differs radically from that for a more hydrophilic statin, pravastatin, of which biliary excretion is largely mediated by Mrp2. These data suggest that the biliary clearance of pitavastatin can be largely accounted for by BCRP in mice. In the case of humans, transcellular transport of pitavastatin was determined in the Madin-Darby canine kidney II cells expressing OATP1B1 and human canalicular efflux transporters. A significant basal-to-apical transport of pitavastatin was observed in OATP1B1/MDR1 and OATP1B1/MRP2 double transfectants as well as OATP1B1/BCRP double transfectants, implying the involvement of multiple transporters in the biliary excretion of pitavastatin in humans. This is in contrast to a previous belief that the biliary excretion of statins is mediated mainly by MRP2.

Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia

“…[12][13][14] BCRP also belongs to the ABC efflux transporter superfamily 26 and is widely expressed in the small intestine, liver and placenta, influencing the absorption and disposition of a variety of substrates. 27,28 It is noteworthy that Petain et al reported that IM clearance in patients carrying the ABCG2 421C/A genotype was significantly lower than in those with the 421C/C genotype. 29 To investigate the role of pharmacogenetic variation in IM metabolism and efficacy, SNPs within important IM exposure genes (ABCB1 (MDR1), ABCC2 (MRP2), ABCG2 (BCRP), CYP3A5, SLC22A1 (OCT1) and SLCO1B3 (OATP1B3)) were analyzed in IM-treated CML patients.…”

Hepatobiliary transporters and drug-induced cholestasis

“…Recently, BCRP has been shown to transport sulfated bile salt conjugates such as taurolithocholate sulfate in vitro 35 and to be involved in the biliary excretion of drugs such as pitavastatin. 36 It might therefore be speculated that BCRP contributes to the hepatocellular excretion of bile salts and xenobiotics. Furthermore, the heterodimeric transporter ABCG5/ABCG8 (ABCG5 and ABCG8) has been identified as the apical transport system involved in the hepatobiliary excretion of plant sterols and cholesterol (reviewed by Klett and Patel 37 and Kosters et al 38 ).…”

Clinical implications of pharmacogenomics of statin treatment

“…34 Hepatobiliary excretion of statins is mediated by ABCC2 and ABCB1 as well as ABCG2 and ABCB11, all of which belong to a family of transporters known to interact with lipophilic xenobiotics. [35][36][37][38][39][40] Variations in these transporters could alter duration of hepatic exposure, and therefore exposure to sites of action and to metabolizing enzymes. Variation in ABCC2, likely the largest contributor to biliary excretion of statins, is known to exhibit variation; however, this has been poorly studied in the context of statin transport.…”