title: 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: 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 metabolite, Ro 48-5033 (4-(2-hydroxy-1,1-dimethyl-ethyl)-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-[2,2']bipyrimidinyl-4-yl]-benzenesulfonamide), as substrates of the human organic anion transporting polypeptides (OATP) OATP1B1 and OATP1B3. Bosentan uptake into Chinese hamster ovary cells expressing these OATP transporters was efficiently inhibited by cyclosporin A and rifampicin with IC(50) values significantly below their effective plasma concentrations in humans. 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.
authors.affiliation: Department of Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. alexander.treiber@actelion.com
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Ralph
authors.initials: R
authors.lastname: Schneiter
authors.forename: Stephanie
authors.initials: S
authors.lastname: Häusler
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D000077300:Bosentan; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016572:Cyclosporine / Q000494:pharmacology*; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D019314:Dehydroepiandrosterone Sulfate / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000378:metabolism; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D015394:Molecular Structure; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism; D012293:Rifampin / Q000494:pharmacology*; D000068677:Sildenafil Citrate; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics; D013450:Sulfones / Q000494:pharmacology*; D014859:Warfarin / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D000077300:Bosentan; D016572:Cyclosporine; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019314:Dehydroepiandrosterone Sulfate; D004791:Enzyme Inhibitors; D004958:Estradiol; D004970:Estrone; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D010879:Piperazines; D011687:Purines; D011743:Pyrimidines; D012293:Rifampin; D000068677:Sildenafil Citrate; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013449:Sulfonamides; D013450:Sulfones; D014859:Warfarin; C120597:Ro 48-5033; D000096926:Benzenesulfonamides; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; C025483:estradiol-17 beta-glucuronide; C450260:CYP2C9 protein, human; C510163:CYP3A4 protein, human; C017296:estrone sulfate