title: In vitro and in vivo studies to characterize the clearance mechanism and potential cytochrome P450 interactions of anidulafungin.
abstract: Anidulafungin is a novel semisynthetic echinocandin with potent activity against Candida (including azole-resistant isolates) and Aspergillus spp. and is used for serious systemic fungal infections. The purpose of these studies was to characterize the clearance mechanism and potential for drug interactions of anidulafungin. Experiments included in vitro degradation of anidulafungin in buffer and human plasma, a bioassay for antifungal activity, in vitro human cytochrome P450 inhibition studies, in vitro incubation with rat and human hepatocytes, and mass balance studies in rats and humans. Clearance of anidulafungin appeared to be primarily due to slow chemical degradation, with no evidence of hepatic-mediated metabolism (phase 1 or 2). Under physiological conditions, further degradation of the primary degradant appears to take place. The primary degradation product does not retain antifungal activity. Anidulafungin was not an inhibitor of cytochrome P450 enzymes commonly involved in drug metabolism. Mass balance studies showed that anidulafungin was eliminated in the feces predominantly as degradation products, with only a small fraction (10%) eliminated as unchanged drug; fecal elimination likely occurred via biliary excretion. Only negligible renal involvement in the drug's elimination was observed. In conclusion, the primary biotransformation of anidulafungin is mediated by slow chemical degradation, with no evidence for hepatic enzymatic metabolism or renal elimination.
authors.affiliation: Pfizer Inc, New York, New York, USA.
authors.forename: Bharat D
authors.initials: BD
authors.lastname: Damle
authors.forename: James A
authors.initials: JA
authors.lastname: Dowell
authors.forename: Robert L
authors.initials: RL
authors.lastname: Walsky
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Weber
authors.forename: Martin
authors.initials: M
authors.lastname: Stogniew
authors.forename: Philip B
authors.initials: PB
authors.lastname: Inskeep
mesh_terms: D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001711:Biotransformation; D001774:Blood Chemical Analysis; D002021:Buffers; D002986:Clinical Trials as Topic; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020128:Inhibitory Concentration 50; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013696:Temperature
chemical_list: D000935:Antifungal Agents; D002021:Buffers; D065607:Cytochrome P-450 Enzyme Inhibitors; D054714:Echinocandins; D003577:Cytochrome P-450 Enzyme System; D000077612:Anidulafungin