Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects

Weber, Cornelia; Schmitt, Rita; Birnboeck, Herbert; Hopfgartner, Gérard; Marle, Sjoerd P. van; Peeters, Pierre; Jonkman, J. H. G.; Jones, C J

doi:10.1016/s0009-9236(96)90127-7

Cited by 223 publications

(233 citation statements)

References 26 publications

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“…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.…”

mentioning

confidence: 99%

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

Treiber

Schneiter²,

Häusler³

et al. 2007

Drug Metab Dispos

279

229

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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...

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confidence: 99%

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

Treiber

Schneiter²,

Häusler³

et al. 2007

Drug Metab Dispos

279

229

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“…No dose adjustment is required in adults based on sex, age, bodyweight or mild hepatic impairment. 17,18 Following oral administration, bosentan reaches peak plasma concentrations after about 3 hours, and it reaches steady state conditions after 3 to 5 days.…”

Section: Pharmacology and Pharmacokinetics Of Bosentanmentioning

confidence: 99%

“…It is metabolized by the hepatic cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C9. 18 Three metabolites are formed, one of which, Ro 48-5033, is biologically active, and may contribute to up to 20% of the parent compound's action. The elimination of unchanged bosentan and its metabolites is primarily through the biliary system, with less than 3% excreted renally.…”

Section: Distribution Metabolism and Eliminationmentioning

confidence: 99%

“…The elimination of unchanged bosentan and its metabolites is primarily through the biliary system, with less than 3% excreted renally. 18 The half-life of bosentan is 5 to 8 hours. 20 Due to its interaction with the cytochrome P450 enzymes, bosentan should be avoided in patients with moderate to severe liver disease or baseline liver transaminases greater than 3 times the upper limit of normal (see Safety and tolerability).…”

Section: Distribution Metabolism and Eliminationmentioning

confidence: 99%

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Safety and tolerability of bosentan in the management of pulmonary arterial hypertension

Roberts¹,

Preston²

2009

DDDT

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Endothelin receptor antagonism has emerged as an important therapeutic approach in pulmonary arterial hypertension (PAH). Bench to bedside scientifi c research has clearly shown that endothelin-1 (ET-1) is over-expressed in several forms of pulmonary vascular disease and plays an important pathogenetic role in the development and progression of PAH. Oral endothelin receptor antagonists (ERAs) have been shown to improve exercise capacity, functional status, pulmonary hemodynamics, and delay the time to clinical worsening in several randomized placebo-controlled trials. Bosentan, the fi rst oral ERA, was approved in 2001 and since that time it has established a strong record of safety and effi cacy in PAH. More recently, two additional ERAs, ambrisentan and sitaxsentan, have been approved for use. The objective of this review is to evaluate the available evidence supporting the effi cacy, pharmacology, safety and tolerability, and patient-focused perspectives for bosentan, the fi rst approved ERA for PAH. Ongoing and forthcoming randomized trials are also highlighted including the application of bosentan in combination with other PAH therapies.

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“…The non-peptide ET A/B antagonist, bosentan, also decreases BP in normotensive humans. 64 Local administration of ET A -receptor antagonists causes greater vasodilatation than local ET A/B antagonism in humans. 14,63 Local forearm ET B -receptor antagonism by BQ-788 causes sustained vasoconstriction in humans, which opposes the vasodilator action of BQ-123.…”

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confidence: 99%

Role of endothelin in cardiovascular disease

Agapitov

Haynes

2002

J Renin Angiotensin Aldosterone Syst

154

119

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Endothelins are a family of peptides, which comprises endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), each containing 21 amino-acids. ET-1 is a peptide secreted mostly by vascular endothelial cells, the predominant isoform expressed in vasculature and the most potent vasoconstrictor currently known. ET-1 also has inotropic, chemotactic and mitogenic properties. In addition, it influences salt and water homeostasis through its effects on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptide and stimulates the sympathetic nervous system.

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Pharmacokinetics and pharmacodynamics of the endothelin-receptor antagonist bosentan in healthy human subjects

Abstract: Bosentan is an orally bioavailable, well-tolerated, and active ET-1 antagonist with a low clearance and a moderate volume of distribution. Its intravenous use is limited because of local intolerability.

Cited by 223 publications

References 26 publications

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

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

Safety and tolerability of bosentan in the management of pulmonary arterial hypertension

Role of endothelin in cardiovascular disease

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