Effect of pregnandiol on caffeine metabolism in female rats.
Three groups of six 5-week-old Sprague Dawley female rats received i.p. injections of pregnandiol, 1.25, 2.50 or 5 mg/kg, respectively, in triolein daily for 7 days. Caffeine metabolism was studied in liver slices on day 8 by HPLC. Only primary metabolites were formed. N-1 demethylation was the most important pathway (theobromine represented 51% of total dimethylxanthines). Unlike in human in vitro or in vivo, 1,3,7-DAU (6-amino-5-(N-formylmethylamino)-1,3-dimethyluracil) was an important metabolite (9.7% of total caffeine metabolites). Pregnandiol inhibited N-1, N-3 and N-7 demethylation in vitro (-33%, -33% and -28%, respectively, at 5 mg/kg/day), but it had no effect on N-1 demethylation at 1.25 or 2.50 mg/kg/day. Pregnandiol at all doses had no effect on 1,3,7-trimethyluric acid and 1,3,7-DAU formation. These results are consistent with the hypothesis that C-8 hydroxylation and demethylation of caffeine are mediated by different isoenzymes. They indicate that pregnandiol is a potent inhibitor of microsomal drug metabolism, specifically of cytochrome P450 IA, which could explain the immaturity of some metabolic pathways of caffeine in neonates.
Bienvenu
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T
Laboratoire de Pharmacologie Périnatale et Pédiatrique, Hôpital Saint Vincent de Paul, Paris, France.
Pons
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Rey
E
E
Thiroux
G
G
Olive
G
G
D000818:Animals; D002110:Caffeine / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006900:Hydroxylation; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000033:anatomy & histology / Q000378:metabolism; D008745:Methylation; D008954:Models, Biological; D010084:Oxidation-Reduction; D011276:Pregnanediol / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D002110:Caffeine; C016836:allopregnane-3,20-diol; D003577:Cytochrome P-450 Enzyme System; D011276:Pregnanediol