Comparison of the effects of liposomal amphotericin B and conventional amphotericin B on propafenone metabolism and hepatic cytochrome P-450 in rats.
The effects of conventional amphotericin B (AmB) dissolved in sodium deoxycholate on microsomal cytochrome P-450 concentrations and propafenone metabolism to 5-hydroxy-propafenone and N-desalkyl-propafenone were compared with those of liposomal AMB (Li-AMB) in rats. AmB (3 mg/kg/day, intravenously [i.v.]) given for 4 days caused a significant decrease in the concentration of hepatic microsomal cytochrome P-450 (0.43 +/- 0.06 nmol/mg versus 0.62 +/- 0. 05 nmol/mg for the control [P < 0.05]). Following the application of Li-AMB (15 mg/kg/day, i.v.), hepatic microsomal cytochrome P-450 concentrations were unchanged at 0.64 +/- 0.08 nmol/mg. AmB decreased ex vivo propafenone metabolism to 5-hydroxy-propafenone and N-desalkyl-propafenone significantly. Sodium deoxycholate (the vehicle of AmB) by itself induced a significant decline of 5-hydroxy-propafenone and N-desalkyl-propafenone production, while microsomal cytochrome P-450 concentrations remained unchanged. In contrast, Li-AMB did not change the levels of production of 5-hydroxy-propafenone or of N-desalkyl-propafenone at either substrate concentration tested (50 micromol and 200 micromol). Microsomal AmB concentrations were significantly higher following Li-AMB application (21.1 +/- 6.2 microg/g versus 3.7 +/- 1.4 microg/g for AmB [P < 0.05]). We conclude that Li-AMB, in contrast to AmB, decreases neither hepatic microsomal cytochrome P-450 nor hepatic propafenone metabolism in rats ex vivo. Sodium deoxycholate alone decreases propafenone metabolism in a similar way to AmB, suggesting that it participates in AmB-induced disturbance of hepatic metabolic function.
Inselmann
G
G
Med. Poliklinik, Universität Würzburg, 97070 Würzburg, Germany.
Volkmann
A
A
Heidemann
H T
HT
D000666:Amphotericin B / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000378:metabolism*; D000935:Antifungal Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003840:Deoxycholic Acid / Q000494:pharmacology; D008081:Liposomes; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011405:Propafenone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000889:Anti-Arrhythmia Agents; D000935:Antifungal Agents; D008081:Liposomes; C068538:liposomal amphotericin B; D003840:Deoxycholic Acid; D011405:Propafenone; D000666:Amphotericin B; D003577:Cytochrome P-450 Enzyme System