Formation of an inactive cytochrome P-450 Fe(II)-metabolite complex after administration of troleandomycin in humans.
In rats, it has been shown that troleandomycin induces its own transformation into a metabolite forming an inactive complex with reduced cytochrome P-450. To determine whether similar effects occur in humans, we studied hepatic microsomes from 6 untreated patients and 6 patients treated with troleandomycin, 2 g per os daily for 7 days. In the treated patients, NADPH-cytochrome c reductase activity was increased by 48%; total cytochrome P-450 concentration was also increased, but 33% of total cytochrome P-450 was complexed by a troleandomycin metabolite. The cytochrome P-450 Fe(II)-metabolite complex exhibited properties identical to those of the inactive complex formed in rats: it exhibited a Soret peak at 456 nm, was unable to bind CO, and was destroyed by addition of 50 microM potassium ferricyanide. We also measured the clearance of antipyrine in 6 other subjects. This clearance was decreased by 45% when measured again on te seventh day of the troleandomycin treatment. We conclude that repeated administration of troleandomycin induces microsomal enzymes, produces an inactive cytochrome P-450 Fe(II)-metabolite complex, and decreases the clearance of antipyrine in humans.
D000328:Adult; D000368:Aged; D000983:Antipyrine / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction; D005260:Female; D005296:Ferrous Compounds / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D014217:Troleandomycin / Q000378:metabolism / Q000494:pharmacology*
D005296:Ferrous Compounds; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D007501:Iron; D000983:Antipyrine