Hormonal regulation of oxidative drug metabolism in the dwarf goat. The effect of sex and hormonal treatment on plasma disposition and metabolite formation of sulphadimidine.
Sulphadimidine (20 mg/kg i.v.) plasma elimination and metabolite formation were studied in intact male, castrated male, and female dwarf goats. Plasma pharmacokinetics and urinary metabolite patterns were first studied in untreated animals. Afterward, females and castrated were treated with a combination of testosterone-propionate (1 mg/kg) and 17 beta-oestradiol-benzoate (0.02 mg/kg) once every 3 days, for a period of 4 weeks. In untreated animals, males showed a considerably lower plasma clearance than females or castrates. This was accompanied by lower partial clearances for the production of two hydroxylated sulphadimidine metabolites. After hormonal treatment of females and castrates, sulphadimidine plasma clearance was significantly reduced, to values corresponding with those observed in control males. Furthermore, hydroxylation was significantly inhibited after treatment. The results indicate that sulphadimidine hydroxylation in the goat is performed by enzymes of the cytochrome P450 complex which are strongly influenced by gonadal hormones. Androgens seem to play a central role in this respect.
Witkamp
R F
RF
Department of Veterinary Basic Sciences, Faculty of Veterinary Medicine, University of Utrecht, The Netherlands.
van 't Klooster
G A
GA
Nijmeijer
S M
SM
Kolker
H J
HJ
Noordhoek
J
J
van Miert
A S
AS
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004334:Drug Administration Schedule; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006041:Goats / Q000378:metabolism*; D006900:Hydroxylation; D008297:Male; D012727:Sex Characteristics; D013418:Sulfamethazine / Q000493:pharmacokinetics*; D013739:Testosterone / Q000494:pharmacology*
D013739:Testosterone; D013418:Sulfamethazine; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; C010452:estradiol-17 beta-benzoate