Acute treatment with pyrrolo(1,4)benzodiazepine antitumor antibiotics alters in vitro hepatic drug metabolizing activity in rats.
The pyrrolo(1,4)benzodiazepine antitumor antibiotic, anthramycin, shares a number of toxicities with the widely used anticancer agent adriamycin. We investigated whether acute doses of anthramycin and the structurally related compounds, sibiromycin and tomaymycin, would depress P-450-dependent drug biotransformations as has been reported for adriamycin. Alterations in drug metabolism rates were determined in rats using 50 and 75% of the approximate 7-day LD50 determined in mice. 4 days post dosing ethylmorphine demethylase and aniline hydroxylase activities in liver 9000 g supernatant were depressed from 26 to 76%. Tomaymycin lowered drug metabolism in a dose-related manner, while sibiromycin produced the greatest amount of depression. Like adriamycin, the pyrrolo(1,4)benzodiazepines possess the ability to depress hepatic drug metabolism and therefore may affect the disposition of compounds with which they are co-administered.
D000617:Aminoglycosides; D000815:Aniline Hydroxylase / Q000378:metabolism; D000818:Animals; D000876:Anthramycin / Q000633:toxicity*; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001570:Benzodiazepinones / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005037:Ethylmorphine-N-Demethylase / Q000378:metabolism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D001570:Benzodiazepinones; D000876:Anthramycin; C100298:sibiromycin; C003619:tomaymycin; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D005037:Ethylmorphine-N-Demethylase