Abstract
(+)-S-145 {5-(+)-(Z)-7-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo[2.2.1]hept-2-yl]-heptenoic acid} and its β-oxidized metabolites {two [bisnor or dihydro (DH)-bisnor] or four (tetranor) carbon-shortened products at the carboxyl side chain} are hydroxylated at the C-5 or C-6 position of the bicyclo ring by microsomal monooxygenases. We investigated the oxidative metabolism of (+)-S-145 and its β-oxidized metabolites with liver microsomes from rats and humans to identify which cytochrome P450 (P450) forms are involved in these reactions. In rats, phenobarbital or dexamethasone treatment significantly increased 5- and 6-hydroxylation activities toward (+)-S-145 and its β-oxidized metabolites, suggesting the involvement of P4503A forms. Immunoinhibition studies suggested that P4503A2 was mainly responsible for the 5-hydroxylation of (+)-S-145, bisnor, and DH-bisnor and the 6-hydroxylation of bisnor and tetranor. Furthermore, P4502C6, a phenobarbital-inducible 2C form in the rat, was involved in the 6-hydroxylation of (+)-S-145, bisnor, and DH-bisnor. P4502C11, the major constitutive form (male rats), was partly involved in the 5-hydroxylation of DH-bisnor and the 6-hydroxylation of bisnor and DH-bisnor. Reconstitution studies with purified human enzymes and immunoinhibition studies suggest that P4503A4 is primarily involved in the 5-hydroxylation of (+)-S-145 and bisnor and the 6-hydroxylation of tetranor; P4502C9/10 mainly catalyzed the 5-hydroxylation of tetranor and the 6-hydroxylation of (+)-S-145. Results of the present study indicated that the same subfamily P450 forms are responsible for the oxidative metabolism of (+)-S-145 in rats and humans. P4503A enzymes were shown to be involved in the formation of 6-hydroxy tetranor, the main metabolite of S-1452 in vivo.
Footnotes
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Send reprint requests to: Yoshitaka Yamaguchi, Department of Drug Metabolism and Disposition, Developmental Research Laboratories, Shionogi & Co., Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka 561, Japan.
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A portion of this study was supported in part by U.S. Public Health Service Grants CA44353, ES00267 (to F.P.G.), and 6H36590 (to R.H.T.).
- Abbreviations used are::
- (+)-S-145
- 5-(+)-(Z)-7-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo[2.2.1]hept-2-yl]-heptenoic acid
- S-1452
- (+)-S-145 calcium dihydrate
- DH-bisnor
- 5-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo-[2.2.1]hept-2-yl]-pentanoic acid
- bisnor
- (3Z)-5-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo-[2.2.1]hept-2-yl]-3-pentenoic acid
- tetranor
- 3-[(1R, 2S, 3S, 4S)-3-phenylsulfonylaminobicyclo-[2.2.1]hept-2yl]-proionic acid
- OH
- hydroxy
- P450
- cytochrome P450
- PB
- phenobarbital
- DEX
- dexamethasone
- DLPC
- dilauroylphosphatidylcholine
- DOPC
- dioleoylphosphatidylcholine
- PS
- phosphatidylserine
- PC
- phosphatidylcholine
- IgG
- immunoglobulin G
- Received May 20, 1996.
- Accepted September 26, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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