Perinatal cimetidine exposure has no apparent effect on hepatic drug oxidative or conjugative activity in adult male rat offspring.
Perinatal exposure of male rat pups to cimetidine has been reported to 'feminize' gonadal and sexual function and to reduce serum testosterone in adult male offspring. This study examined whether perinatal cimetidine exposure altered the androgen 'imprinting' of sex differences in mature male hepatic biotransformation capacities. During the perinatal period, dams were infused with cimetidine (18 mg/kg/day) through Alzet osmotic pumps placed subcutaneously beginning at 10 days of gestation. Pump function was confirmed by weekly high-performance liquid chromatographic analysis of maternal urine for unchanged cimetidine. Male pups were culled at birth with continued exposure to cimetidine in breast milk until weaning. At about 100 days of age, in vitro and in vivo drug oxidative and conjugative activities were measured in mature males. Early cimetidine exposure did not alter hepatic oxidative (cytochrome P-450 content or monooxygenase activity) or conjugative (UDP-glucuronosyltransferase activity towards testosterone, morphine, 1-naphthol, estrone, or sulfotransferase activity towards acetaminophen or glycolithocholate) capacities in mature males. Two sulfotransferase isoenzyme activities (acetaminophen sulfotransferase 2 and bile salt sulfotransferase I) previously shown to be regulated by gonadal hormones were also unchanged. Serum testosterone was unaffected by perinatal cimetidine exposure. Moreover, there were no effects of perinatal cimetidine exposure on in vivo pharmacokinetics or metabolic fate of acetaminophen.


CONCLUSIONS
Perinatal exposure of male pups to doses of cimetidine similar to those used in humans did not appear to affect the imprinting of sex differences on in vitro hepatic drug metabolism or elimination kinetics of acetaminophen.
Kane
R E
RE
Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City.
Lamott
J
J
Franklin
M R
MR
Galinsky
R E
RE
D000082:Acetaminophen / Q000493:pharmacokinetics; D000818:Animals; D015239:Arylsulfotransferase / Q000378:metabolism; D001711:Biotransformation; D002848:Chromatography, DEAE-Cellulose; D002852:Chromatography, Ion Exchange; D002927:Cimetidine / Q000009:adverse effects*; D005260:Female; D008099:Liver / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D000082:Acetaminophen; D002927:Cimetidine; D015239:Arylsulfotransferase