Identification of cytochromes P450 involved in the human liver microsomal metabolism of the thromboxane A2 inhibitor seratrodast (ABT-001).
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Kumar GN, Dubberke E, Rodrigues AD, Roberts E, Dennisen JF
Identification of cytochromes P450 involved in the human liver microsomal metabolism of the thromboxane A2 inhibitor seratrodast (ABT-001).
Drug Metab Dispos. 1997 Jan;25(1):110-5.
- PubMed ID
- 9010637 [ View in PubMed]
- Abstract
Seratrodast (ABT-001, AA-2414) undergoes cytochrome P450 (CYP)-dependent metabolism to a major (5-methylhydroxy seratrodast; 5-HOS) and a minor 4'-hydroxy seratrodast metabolite in human liver microsomes. The mean apparent K(m) and Vmax for the formation of 5-HOS were 15.5 microM and 589.0 pmol 5-HOS formed/mg protein/min, respectively. Chemical inhibition using isoform-selective CYP inhibitors, correlation of 5-HOS formation with several isoform-specific CYP activities in a panel of liver microsomes, metabolism by microsomes derived from CYP cDNA-expressed B-lymphoblastoid cells, and immunoinhibition by isoform-specific anti-CYP antibodies indicated that 5-HOS formation is catalyzed by CYP3A and CYP2C9/10, with a minor contribution from CYP2C8 and CYP2C19. At clinically relevant concentrations, seratrodast was found to inhibit tolbutamide methylhydroxylation (IC50 = 60 microM), (S)-mephenytoin 4'-hydroxylation (IC50 = 50 microM), and coumarin 7-hydroxylation (IC60 = 95 microM), indicating the potential for significant clinical interactions. The inducers of CYP3A and/or CYP2C9 (e.g. rifampicin and phenytoin) are likely to alter the disposition of seratrodast.
DrugBank Data that Cites this Article
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Seratrodast Cytochrome P450 2C19 Protein Humans UnknownSubstrateDetails Seratrodast Cytochrome P450 2C8 Protein Humans UnknownSubstrateDetails Seratrodast Cytochrome P450 2C9 Protein Humans UnknownSubstrateDetails Seratrodast Cytochrome P450 3A4 Protein Humans UnknownSubstrateInducerDetails