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 Km andVmax for the formation of 5-HOS were 15.5 μM 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 μM), (S)-mephenytoin 4′-hydroxylation (IC50 = 50 μM), and coumarin 7-hydroxylation (IC50 = 95 μM), 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.
Footnotes
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Send reprint requests to: Dr. Gondi N. Kumar, Biotransformation Department, D-46V, AP9, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-3500.
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This study was supported by TAP Holdings, Inc. E.D. was the recipient of an Abbott Summer (1995) Research Internship.
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↵2 Dr. J. M. Lasker, personal communication, 1996.
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↵3 Dr. E. Samara, personal communication, 1996.
- Abbreviations used are::
- 5-HOS
- 5-methylhydroxy seratrodast
- 4′-HOS
- 4′-hydroxy seratrodast
- MTT
- 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
- CYP
- cytochrome P450
- IgG
- immunoglobulin G
- CLint
- intrinsic clearance
- Vmax
- maximum initial velocity
- Km
- Michaelis constant
- IC50
- concentration that inhibited 50% of the activity
- Received June 28, 1996.
- Accepted October 10, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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