Comparison of the Effects of Liposomal Amphotericin B and Conventional Amphotericin B on Propafenone Metabolism and Hepatic Cytochrome P-450 in Rats

Abstract

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-desalkylpropafenone 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 Ndesalkyl-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 mol and 200 mol). Microsomal AmB concentrations were significantly higher following Li-AMB application (21.1 ؎ 6.2 g/g versus 3.7 ؎ 1.4 g/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.The polyene macrolide amphotericin B is the most effective antibiotic agent used for the treatment of systemic fungal infections in humans (13). However, its clinical use is limited due to its pronounced side effects such as chills, fever, nausea, and organ damage (especially the impairment of kidney function). Amphotericin B has a high affinity for biological membranes, resulting in binding to sterols, which is most likely responsible for its excellent antifungal properties. On the other hand, this activity may potentially alter cellular membrane functions, resulting in organ dysfunction. The distribution of amphotericin B differs widely between organs, and the highest amphotericin B concentrations are reached in the liver (2) with the potential to alter hepatic cellular integrity (12). In perfused rat livers, it has been demonstrated that amphotericin B reduces bile flow and decreases bile acid secretion (6). Studies performed with human liver microsomes suggest that amphotericin alters hepatic metabolic function and results in a decrease of antipyrine clearance (7). However, the effect of amphotericin B on hepatic metabolic function is not known in detail. To overcome the pronounced side effects of conventional amphotericin B, novel lipid-containing formulations of amphotericin B with fewer side effects have been developed. These formulations include the small unilamellar vesicle liposomal amphotericin B known as AmBisome, which has ...

Pharmacokinetics Characterization of Liposomal Amphotericin B: Investigation of Clearance Process and Drug Interaction Potential

“…Inaddition,othermeasured parameters related todrugmetabolizing enzyme systemsw erenotchanged significantlycompared withthosei nthe control group. Itw as previouslyr eported thatD-AMB, but notL-AMB, influ-encesmicrosomalCYP concentrationsin rats,whichi s consistentw itho ur presentr esults [28].Inf act,in human,interactionsbetween L-AMB and co-administered drugswithregardtodrug-metabolizing enzyme systems haven otbeen reported,whichwass upported byour presents tudy.…”

Evaluation of Amphotericin B and Chloramphenicol as Alternative Drugs for Treatment of Chytridiomycosis and Their Impacts on Innate Skin Defenses

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Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

“…Vice versa, selective inhibition of CYP450 enzymes was observed in rats treated with D-AMB, assumed to be due to an impairment of monooxygenases on the endoplasmic reticulum [ 106 ]. This inhibitory effect on CYP450 activity was confirmed in humans [ 107 ].…”