Bosentan Cyclosporine

Several experimental systems to check the inhibition potency of bile add transport have been characterized. Using sandwich-cultured human hepatocytes, bosentan, cyclosporin A, CI-1034 (endothelin-A receptor antagonist), glyburide, erythromycin estolate, and troleandomycin could inhibit the taurocholate efflux to the bile pocket [234]. Moreover, Mita et al. [235] construded NTCP/BSEP double-transfeded cells and some cholestasis-induced compounds inhibited both the NTCP-mediated uptake and the BSEP-mediated efflux of taurocholate. Then, they have found fluorescent bile acids whose transcellular transport was dearly observed, which may be used for the rapid identification of inhibitors of NTCP and BSEP in drug screening process [235]. 

Drugs that may affect cyclosporine include allopurinol, amiodarone, androgens (eg, danazol, methyltestosterone), anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin), azole antifungals (eg, fluconazole, ketoconazole), beta-blockers, bosentan, bromocriptine, calcium channel blockers, colchicine, oral contraceptives, corticosteroids, fluoroquinolones (eg, ciprofloxacin), foscarnet, HMG-CoA reductase inhibitors, imipenem-cilastatin, macrolide antibiotics, methotrexate, metoclopramide, nafcillin, nefazodone, orlistat, potassium-sparing diuretics, probucol, rifamycins (rifampin, rifabutin), serotonin reuptake inhibitors (SSRIs eg, fluoxetine, sertraline),... 

Drugs that may be affected by cyclosporine include bosentan, digoxin, etopisode, and HMG-CoA reductase inhibitors, methotrexate, potassium-sparing diuretics, and sirolimus. 

Treiber A, Schneiter R, Delahaye S, et al. Inhibition of organic anion transporting polypeptide-mediated hepatic uptake is the major determinant in the pharmacokinetic interaction between bosentan and cyclosporin A in the rat. J Pharmacol Exp Ther 2004 308 1121-1129. 

Sitaxsentan is a potent and selective agent which inhibits ET-1 binding to ETA receptors (IC50 = 1.4 nM), while being essentially inactive at ETB receptors (IC50 = 9.8 pM).23 In the clinic, it was found to have excellent oral bioavailability (70-100%) and a terminal elimination half-life of 10 h, and is administered as a once daily 100 mg dose. It is highly protein bound in plasma (> 99%) and extensively metabolized in the liver to inactive metabolites, predominantly by CYPs 2C9 and 3A4. Excretion is 50 60% renal, with the balance in the feces.25 Sitaxsentan inhibits CYP 2C9, and was observed to increase exposure to warfarin by over twofold. The use of cyclosporine A is also contraindicated, but no interactions were observed with sildenafil.15 Sitaxsentan was well tolerated in trials, with only minor side effects reported. Reversible liver enzyme abnormalities were also observed, but less frequently than with bosentan.15 25... 

Bosentan Increased bosentan levels and risk of toxicity and also decreased cyclosporine levels and efficacy... 

Binet I, Wallnofer A, Weber C, Jones R, Thiel G. Renal hemodynamics and pharmacokinetics of bosentan with and without cyclosporine A. Kidney Int 2000 57 224-231. 

Clinically important, potentially hazardous interactions with azithromycin, bosentan, ciprofibrate, clarithromycin, clopidogrel, cyclosporine, erythromycin, fosamprenavir, fusidic acid, gemfibrozil, imatinib, itraconazole, lopinavir, niacin, quinine, red rice yeast, telithromycin, verapamil... 

Treiber, A., Schneiter, R., Hausler, S. and Stieger, B. (2007) 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. Drug Metabolism and Disposition The Biological Fate of Chemicals, 35, 1400-1407. 

Pure cholestasis without hepatitis is observed most frequently with contraceptives and 17a-alkylated androgenic steroids, and the mechanism most likely involves interference with hepatocyte canalicular efflux systems for bile salts, organic anions, and phospholipids. The rate-limiting step in bile formation is considered to be the bile salt export pump (BSEP)-mediated translocation of bile salts across the canalicular hepatocyte membrane. Inhibition of BSEP function by metabolites of cyclosporine A, troglitazone, bosentan, rifampicin, and sex steroids is an important cause of drug induced cholestasis (Kullak-Ublick, 2004). 

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