In vitro and in vivo pharmacokinetic characteristics of clazosentan, an intravenous endothelin receptor antagonist, in humans.
OBJECTIVE
In this study, the distribution, metabolism and excretion of the endothelin receptor antagonist clazosentan were investigated.


METHODS
4 healthy male subjects received an intravenous 3-h infusion at a rate of 0.2 mg/kg/h of 14C-labeled clazosentan and blood, urine and feces samples were collected for a period of 8 days. Experiments were performed to investigate the plasma protein binding, the binding to red blood cells and the inhibition potential of cytochrome P450 isoenzymes of clazosentan.


RESULTS
Clazosentan was mainly excreted unchanged into feces whereas about 15% of the radioactive dose was recovered in urine. No metabolites representing more than 5% of total radioactivity were identified. No relevant inhibition of the human cytochrome P450 isoenzymes, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4, was observed in vitro at clazosentan concentrations largely exceeding those observed in clinical trials. In human blood, clazosentan was highly bound to plasma proteins and did hardly penetrate into red blood cells.


CONCLUSIONS
The primary route of excretion of clazosentan was via the feces, mainly as unchanged drug.
van Giersbergen
P L M
PL
Department of Clinical Pharmacology, Actelin Pharmaceuticals Ltd., Allschwil, Switzerland.
Treiber
A
A
Dingemanse
J
J
D000328:Adult; D001798:Blood Proteins / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004146:Dioxanes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D065130:Endothelin A Receptor Antagonists; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011485:Protein Binding; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D044022:Receptor, Endothelin A / Q000378:metabolism; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014018:Tissue Distribution
D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D004146:Dioxanes; D065130:Endothelin A Receptor Antagonists; D007527:Isoenzymes; D011725:Pyridines; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; D013777:Tetrazoles; C109641:clazosentan; D003577:Cytochrome P-450 Enzyme System