In vivo and in vitro disposition profile of tezosentan, an intravenous dual endothelin receptor antagonist, in humans.
1. The plasma concentration-time profile of the (14)C-labelled endothelin receptor antagonist tezosentan in healthy male volunteers after a 1-h infusion at 100 mg h(-1) followed a biphasic decline with half-lives of 3-5 min for the initial disposition phase and approximately 4 h for the terminal phase. 2. Tezosentan was predominantly excreted unchanged into faeces, whereas less than 5% of the dose was excreted as unchanged drug in urine. Two isomeric, hydroxylated metabolites (M1, M2) were detected in faeces representing 2-5% of the total radioactivity. 3. In vitro, with human liver microsomes and primary hepatocytes, tezosentan was metabolized at very low rates. Upon prolonged incubation with human hepatocytes for 24 h, formation of the hydroxylated metabolite M1 and a glucuronic acid conjugate, M3, was observed. 4. No relevant inhibition of the human cytochrome P450 (CYP) forms, CYP1A2, 2C9, 2C19, 2D6 and 3A4, was observed in vitro at tezosentan concentrations largely exceeding those observed in clinical trials. 5. In human blood, tezosentan was highly bound to plasma proteins, mainly albumin, and hardly penetrated into red blood cells.
Actelion Pharmaceuticals Ltd, Departments of Preclinical Pharmacokinetics and Metabolism, and Clinical Pharmacology, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
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A
Treiber
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PL
Van Giersbergen
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J
Dingemanse
D001711:Biotransformation; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D004562:Electrocardiography; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D011485:Protein Binding; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D004791:Enzyme Inhibitors; D020719:Glucuronides; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan