Effect of glutathione depletion on the in vivo inhibition of drug metabolism by agents forming an inactive cytochrome P-450 Fe(II):metabolite complex. Studies with amiodarone and troleandomycin.
The relative contribution of competitive inhibition versus formation of a P-450:metabolite complex to the in vivo inhibition of drug metabolism for several agents is unclear. The present investigation examined the contribution of these two mechanisms to the in vivo inhibition of drug metabolism by amiodarone through manipulation of glutathione turnover. In vivo P-450-dependent metabolism in rats was assessed by determining antipyrine clearance. Pretreatment with amiodarone (50 mg/kg, iv) decreased antipyrine clearance with or without prior glutathione depletion. Depletion of glutathione by buthionine sulfoximine (1.6 g/kg, ip) did not enhance the magnitude of inhibition of antipyrine clearance by amiodarone. Moreover, administration of a normally subinhibitory dose of amiodarone after buthionine sulfoximine pretreatment did not influence antipyrine clearance. Similarly, depletion of glutathione via buthionine sulfoximine or diethylmaleate (1 mL/kg, po) did not influence the magnitude of inhibition caused by a single po dose of troleandomycin (500 or 350 mg/kg, respectively). These data indicate that glutathione content may not be a critical determinant for the in vivo inhibition of drug metabolism by agents which form a P-450:metabolite complex.
Svensson
C K
CK
Department of Pharmaceutical Sciences, College of Pharmacy & Allied Health Professions, Wayne State University, Detroit, MI 48202.
Drobitch
R K
RK
Kloss
K A
KA
D000638:Amiodarone / Q000378:metabolism*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000983:Antipyrine / Q000378:metabolism; D019328:Buthionine Sulfoximine; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005978:Glutathione / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014217:Troleandomycin / Q000378:metabolism*
D000963:Antimetabolites; D008298:Maleates; D004364:Pharmaceutical Preparations; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; C014476:diethyl maleate; D005978:Glutathione; D000638:Amiodarone; D000983:Antipyrine