Bosentan Is a Substrate of Human OATP1B1 and OATP1B3: Inhibition of Hepatic Uptake as the Common Mechanism of Its Interactions with Cyclosporin A, Rifampicin, and Sildenafil

Abstract

ABSTRACT:The elimination process of the endothelin receptor antagonist bosentan (Tracleer) in humans is entirely dependent on metabolism mediated by two cytochrome P450 (P450) enzymes, i.e., CYP3A4 and CYP2C9. Most interactions with concomitantly administered drugs can be rationalized in terms of inhibition of these P450 enzymes. The increased bosentan concentrations observed in the presence of cyclosporin A, rifampicin, or sildenafil, however, are incompatible with this paradigm and prompted the search for alternative mechanisms governing these interactions. In the present article, we identify bosentan and its active plasma The phosphodiesterase-5 inhibitor sildenafil was also shown to interfere with OATP-mediated transport, however, at concentrations above those achieved in therapeutic use. Therefore, inhibition of bosentan hepatic uptake may represent an alternative/complementary mechanism to rationalize some of the pharmacokinetic interactions seen in therapeutic use. A similar picture has been drawn for drugs like pitavastatin and fexofenadine, drugs that are mainly excreted in unchanged form. Bosentan elimination, in contrast, is entirely dependent on metabolism. Therefore, the described interactions with rifampicin, cyclosporin A, and, to a lesser extent, sildenafil represent evidence that inhibition of hepatic uptake may become the rate-limiting step in the overall elimination process even for drugs whose elimination is entirely dependent on metabolism.Bosentan (Tracleer) is a dual endothelin receptor antagonist (Clozel et al., 1994;Neidhart et al., 1996) approved as the first oral treatment for pulmonary arterial hypertension (PAH) (Rubin et al., 2002). Its pharmacokinetic profile in humans is characterized by a low systemic plasma clearance of 17 l/h, a volume of distribution of about 30 l, and an oral bioavailability of about 50% (Dingemanse and van . At the maintenance dose of 125 mg b.i.d., bosentan trough concentrations decrease during the first days of treatment as a result of autoinduction of metabolizing enzymes, leading to an about 40% lower exposure at steady state. Bosentan is metabolized in the liver (Fig. 1), mediated to a similar extent by CYP2C9 and CYP3A4, followed by subsequent biliary excretion.Hydroxylation at the t-butyl group by CYP2C9 and CYP3A4 yields metabolite Ro 48-5033, a metabolite that retains pharmacological activity and is present in human plasma at levels of about 10% compared with parent bosentan. Ro 47-8634 is formed by oxidative demethylation of the guaiacol ether, catalyzed by CYP3A4, to the corresponding phenol, whereas metabolite Ro 64-1056 is formed as a minor product from both primary metabolites. Renal clearance of bosentan is negligible (Hopfgartner et al., 1996;Weber et al., 1999b). Based on preclinical data, the first-pass effect of bosentan is small. Bosentan is neither a substrate nor an inhibitor of the intestinal efflux pump MDR1 (P-glycoprotein, ABCB1) (Weber et al., 1999a;Treiber et al., 2004).Most of the pharmacokinetic drug-drug interactions observed w...

Transporters involved in the hepatic uptake of 99mTc-mebrofenin and indocyanine green

“…Although the mM-range of K m implies a relatively low affinity for 99m Tc- mebrofenin in comparison to 49 50 51 52 53 54 55 56 57 58 59 60 61 62 other OATP1B1 and OATP1B3 substrates (18,24), the intrinsic transport capacities (V max /K m ) of OATP1B1 and OATP1B3 indicate that the transport of 99m Tc-mebrofenin is highly effective.…”

“…Cell Lines Chinese hamster ovary (CHO) cell lines stably expressing human OATP1B1, OATP1B3, and OATP2B1 have been described (17,18). CHO wild type (CHO-WT) cells were used as control.…”

“…fetal calf serum, 0.05mg/mL L-proline, 100U/mL penicillin/streptomycin, and 500Pg/mL geneticin G- (17,18). Flp-In CHO cells (pcDNA5/FRT and NTCP) were grown in HAM F-12 medium containing 10% fetal calf serum, 1mM L-glutamine, 100U/mL penicillin/streptomycin, and 500Pg/mL hygromycin B.…”

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

“…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 …”

Potential role of organic anion transporting polypeptide 1B1 (OATP1B1) in the selective hepatic uptake of hematoporphyrin monomethyl ether isomers

“…OATP1B1 and OATP1B3 are the predominant OATP isoforms expressed in the liver, and they are involved in the uptake of multiple endogenous and exogenous compounds, including bilirubin [5] , bosentan [6,7] , and statins [8][9][10] . Additionally, OATP2B1-mediated selective scutellarin uptake plays a key role in the much lower exposure of scutellarin than that of isoscutellarin in humans [11] .…”