Interaction of HIV protease inhibitors with OATP1B1, 1B3, and 2B1

Abstract

The effects of human immunodeficiency virus (HIV) protease inhibitors (PI) on the accumulation of the fluorescent bile salt analogue cholyl-glycylamido-fluorescein (CGamF) were determined in organic anion transporting polypeptide (OATP)-1B1 and -1B3-expressing Chinese hamster ovary (CHO) cells. In addition, interaction studies in Caco-2 monolayers, known only to express the OATP2B1 isoform, were conducted using the established OATP substrate estrone 3-sulfate (E3S), since no CGamF accumulation was observed in Caco-2 monolayers. CGamF appeared an excellent substrate for the OATP1B subfamily, with net accumulation clearance values of 7.8 and 142 microl min(-1) mg(-1) protein in OATP1B1 and OATP1B3-transfected cells, respectively. K(i)-values reflecting inhibition of CGamF accumulation by HIV PI correlated well between OATP1B1 and OATP1B3-expressing cells. Lopinavir was the most potent inhibitor (K(i) = 0.5-1.4 microM) of OATP1B-mediated CGamF accumulation compared with atazanavir, darunavir, ritonavir, and saquinavir (K(i) between 1.4 and 3.3 microM). Inhibitory profiles towards OATP2B1-mediated E3S accumulation were different with only indinavir, saquinavir, and ritonavir showing substantial effects. In conclusion, OATP1B3 appears to be a major transport mechanism mediating sodium-independent CGamF accumulation in human liver, and CGamF could be used as a probe substrate for in vitro drug interaction studies. The remarkably potent inhibition of OATP1B1 by lopinavir may explain some clinically relevant drug interactions between lopinavir and OATP1B substrates such as fexofenadine.

Novel Mechanism of Impaired Function of Organic Anion-Transporting Polypeptide 1B3 in Human Hepatocytes: Post-Translational Regulation of OATP1B3 by Protein Kinase C Activation

“…As shown in Fig. 4B, in both nontransduced (None) and Ad-OATP1B3-transduced human SCH (Ad-OATP1B3), PKC activation by PMA treatment (0.1 mM, 30 minutes) significantly inhibited [ 3 H]CCK-8 accumulation to an extent close to the inhibition by 100 mM BSP, a potent inhibitor of OATPs (Annaert et al, 2010).…”

“…Recently, OATP1B1 and OATP1B3 have been recognized as important determinants of transport-mediated drug-drug interactions (DDIs) (Tweedie et al, 2013). Many drugs that are potent OATP inhibitors in vitro [e.g., cyclosporine (Letschert et al, 2006) and ritonavir (Annaert et al, 2010)] may cause clinically significant DDIs in vivo; for example, significant increases in the systemic exposure of statins have been reported when these OATP inhibitors are coadministered with statins, which are OATP substrates (Shitara et al, 2003;Kiser et al, 2008). OATP1B3 shares a variety of common substrates with OATP1B1, such as statins (Hirano et al, 2004;Kitamura et al, 2008), rifampicin (Vavricka et al, 2002), and bromosulfophthalein (BSP) (Cui et al, 2001).…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…[178,179] Thus, the inhibition of the enterocytic influx via OSTa/b is probably not of concern with regards to DDIs. However, OSTa/b is also an intestinal basolateral absorptive transporter (along [165,168] 4.0/4.6 a Simvastatin [164] 85 a Tipranavir [165] 0.9 a OATP3A1_v1 (OATP-D)…”

“…Atorvastatin [164] 0.2 Atazanavir [165] 3.6 a Estriol [158] Benzylpenicillin [35] Atorvastatin [164] 0.7 Pregnenolone sulfate [158] Estrone [158] Bosentan [166] 202 Benzylpenicillin [36] 16 000 a Prostaglandin E2 [35] Pregnenolone sulfate [157,158] 3.5 a Fexofenadine [41] Cerivastatin [164] 66 a Taurocholate [41] 72 Testosterone [158] 15 a /21 a Fluvastatin [162,167] 0.7 Cimetidine [36] Glibenclamide [163] 6.3 Ciclosporin [154] 0.07 a Pitavastatin [161] 1.2 Darunavir [165] 26 a Pravastatin [37,41] 2250 Digoxin [164] Rosuvastatin [87,154] 2.4/6.4 Efavirenz [165] 9.6 a Tebipenem pivoxil [156] >1000 Gemfibrozil [154,162,164] 8 a Glibenclamide [164] Indinavir [168] 3.0 Indometacin [36,164] Lopinavir [165] 0.7 a Lovastatin [164] Memantine [164] Mifepristone [158] 2.2 a /4.7 a Nelfinavir [165] 0.9 a Pravastatin [36,37] 5 500 a /1 020 a Probenecid …”

Clearance Prediction of HIV Protease Inhibitors in Man: Role of Hepatic Uptake

“…12,13 Several studies have illustrated that HIV PI inhibit the in vitro cellular uptake of OATP1B probe substrates like estradiol-17β-D-glucuronide, CGamF and sodium fluorescein. [14][15][16][17] Moreover, it has been suggested that inhibition of these membrane transporters contributes to clinically important antiretroviral drug-drug interactions, for example with cerivastatin and atorvastatin. 18 While these examples certainly illustrate the clinical relevance of OATP modulation by HIV PI, the concept of meaningful OATPmediated transport of HIV PI remains controversial.…”