Induction of cytochromes P-450 2B and 3A in mice following the dietary administration of the novel cognitive enhancer linopirdine

S Diamond, D Rakestraw, J O'Neil, GN Lam and DD Christ

Section of The Du Pont Merck Pharmaceutical Company, Stine-Haskell Research Center, Newark, DE 19714.

The effects of the novel cognitive enhancer linopirdine [3,3-bis(4- pyridinylmethyl)-1-phenylindolin-2-one] on hepatic cytochromes P-450 (CYP) and linopirdine metabolism were determined in female mice fed 0, 10, 50, and 250 mg/kg/day of linopirdine in the diet for 4, 7, 14, and 28 days. Linopirdine induced CYP maximally by day 4 only at the highest dose, as demonstrated by significant (p < 0.05) increases in total spectral CYP and liver weight. SDS-PAGE revealed induced 52 kDa microsomal protein(s), identified as CYP2B and 3A by immunoblotting. Linopirdine also increased the rates of reactions selectively catalyzed by CYP2B and 3A (pentoxyresorufin O-dealkylation, benzphetamine N- demethylation, erythromycin N-demethylation, and testosterone 2 beta-, 6 beta-, 16 beta-hydroxylation), 1.7- to 3.0-fold vs. control, similar to increases produced by the prototypical CYP2B and 3A inducers phenobarbital and dexamethasone. No increase in microsomal CYP1A or 2E levels was demonstrated by immunoblotting or selective substrate assays. CYP induction increased the metabolism of linopirdine. The area under the plasma concentration-time curve of linopirdine after a 250 mg/kg/day dose decreased 11-fold from day 1-28, and microsomes from a parallel 250 mg/kg/day group metabolized linopirdine 1.9-fold faster than control (p < 0.05). This autoinduction was due primarily to the induced CYP3A, because antibodies recognizing CYP3A inhibited the microsomal metabolism of linopirdine by 85%, whereas antibodies to CYP2B were not inhibitory. In summary, the dietary consumption of 250 mg/kg/day of linopirdine by female mice coinduced CYP2B and 3A maximally by day 4, and resulted in an increased rate of metabolism of linopirdine, predominantly due to CYP3A.

Volume 22, Issue 1, pp. 65-73, 01/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				M. F. Grubb, S. Diamond, and D. D. Christ In Vitro and In Vivo Effects of the Arylamine Human Immunodeficiency Virus Protease Inhibitor 4R-(4alpha ,5alpha ,6beta ,7beta )-1-[(3-(1-Imidazoylcarbamoyl)phenyl)methyl]-3-[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one (SD894) on Rat Hepatic Cytochrome P450 2B and 3A Drug Metab. Dispos., December 1, 1997; 25(12): 1424 - 1428. [Abstract] [Full Text]