Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.

Article Details

Citation

Dingemanse J, Schaarschmidt D, van Giersbergen PL

Investigation of the mutual pharmacokinetic interactions between bosentan, a dual endothelin receptor antagonist, and simvastatin.

Clin Pharmacokinet. 2003;42(3):293-301.

PubMed ID
12603176 [ View in PubMed
]
Abstract

BACKGROUND: In vitro, bosentan has been shown to be a mild inducer of cytochrome P450 (CYP) 2C9 and 3A4. PURPOSE: To investigate in vivo the mutual pharmacokinetic interactions between bosentan and simvastatin, a CYP3A4 substrate. METHODS: Nine healthy male subjects were treated in a three-period randomised crossover study with: (A) bosentan 125 mg twice daily for 5.5 days; (B) simvastatin 40 mg once daily for 6 days; and (C) bosentan 125 mg twice daily and simvastatin 40 mg once daily for 5.5 and 6 days, respectively. Plasma concentration-time profiles of bosentan and its metabolites (treatments A and C) and simvastatin and beta-hydroxyacid simvastatin (treatments B and C) were determined on day 6. RESULTS: Steady-state conditions for bosentan and its metabolites were attained on day 4 of treatment. The pharmacokinetic parameters of bosentan and its metabolites were not influenced by concomitant treatment with simvastatin: areas under the plasma concentration-time curve over one administration interval of 12 hours (AUC(tau)) [geometric mean and 95% CI] were 4586 (3719-5656) and 4928 (3945-6156) micro g * h/L. In contrast, bosentan significantly reduced exposure to simvastatin and beta-hydroxyacid simvastatin by 34 and 46%, respectively. AUC(tau) values for simvastatin were 30.5 (23.1-40.2) and 20.0 (15.9-25.1) micro g * h/L and for beta-hydroxyacid simvastatin 43.0 (32.1-57.8) and 23.4 (16.7-32.6) micro g * h/L in treatments B and C, respectively. CONCLUSIONS: Concomitant treatment with bosentan reduces the exposure to simvastatin and beta-hydroxyacid simvastatin by approximately 40%, indicating that in vivo bosentan is also a mild inducer of CYP3A4.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
BosentanCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Inducer
Details
Drug Interactions
DrugsInteraction
Atorvastatin
Bosentan
The serum concentration of Atorvastatin can be decreased when it is combined with Bosentan.
Fluvastatin
Bosentan
The serum concentration of Fluvastatin can be decreased when it is combined with Bosentan.
Lovastatin
Bosentan
The serum concentration of Lovastatin can be decreased when it is combined with Bosentan.
Pravastatin
Bosentan
The serum concentration of Pravastatin can be decreased when it is combined with Bosentan.
Rosuvastatin
Bosentan
The serum concentration of Rosuvastatin can be decreased when it is combined with Bosentan.