Identification of cytochromes P450 involved in the human liver microsomal metabolism of the thromboxane A2 inhibitor seratrodast (ABT-001).
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.
Kumar
G N
GN
Biotransformation Department, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Dubberke
E
E
Rodrigues
A D
AD
Roberts
E
E
Dennisen
J F
JF
D018927:Anti-Asthmatic Agents / Q000378:metabolism*; D000906:Antibodies / Q000494:pharmacology; D001402:B-Lymphocytes / Q000201:enzymology; D016227:Benzoquinones / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006538:Heptanoic Acids / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism*; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D013379:Substrate Specificity; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*
D018927:Anti-Asthmatic Agents; D000906:Antibodies; D016227:Benzoquinones; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D007527:Isoenzymes; C060230:seratrodast; D013928:Thromboxane A2; D003577:Cytochrome P-450 Enzyme System