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The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro

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Author: Parnham, M.J. · Bogaards, J.J.P. · Schrander, F. · Schut, M.W. · Orešković, K. · Mildner, B.
Type:article
Date:2005
Institution: TNO Kwaliteit van Leven
Source:Biopharmaceutics and Drug Disposition, 1, 26, 27-33
Identifier: 238297
doi: doi:10.1002/bdd.429
Keywords: Health Pharmacology · Physiological Sciences · Cytochrome P450 · Metabolism · PLD-118 · 2 amino 4 methylenecyclopentanecarboxylic acid · alpha naphthoflavone · amino acid · antifungal agent · bufuralol · chlorzoxazone · coumarin · cytochrome P450 · cytochrome P450 1A2 · cytochrome P450 2A6 · cytochrome P450 2B6 · cytochrome P450 2C19 · cytochrome P450 2C9 · cytochrome P450 2D6 · cytochrome P450 2E1 · cytochrome P450 3A · diclofenac · diethyldithiocarbamic acid · ethoxyresorufin · ketoconazole · mephenytoin · monoclonal antibody · monoclonal antibody 2B6 · quinidine · reduced nicotinamide adenine dinucleotide phosphate · resorufin · sulfaphenazole · testosterone · umbelliferone · unclassified drug · unindexed drug · analytic method · animal tissue · article · candidiasis · concentration response · controlled study · derivatization · dog · drug structure · enzyme assay · enzyme inhibition · enzyme stability · enzyme substrate · fluorescence analysis · high performance liquid chromatography · human · human tissue · in vitro study · liver homogenate · liver microsome metabolism · nonhuman · rat · structure analysis · Administration, Oral · Animals · Antifungal Agents · Chemistry, Pharmaceutical · Cycloleucine · Cytochrome P-450 Enzyme System · Dogs · Drug Evaluation, Preclinical · Humans · Microsomes, Liver · Rats · Ribosomal Proteins

Abstract

PLD-118 is a novel, oral antifungal drug, under development for the treatment of Candida infections. Possible metabolism of PLD-118 by rat, dog and human S9 liver homogenates and inhibition of human cytochrome P450 (CYP) enzymes were investigated. PLD-118 (10 and 100 μm) incubated for 0-60 min with S9 fractions and NADPH was determined by HPLC, using the Waters AccQ.Tag method after derivatization of amino acids to stable, fluorescent derivatives. CYP assays were performed using pooled human liver microsomes with substrates, selective towards human CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, incubated at concentrations around the Km. Incubation mixtures were preincubated with PLD-118 (0.1-100 μM) or control inhibitor for 5 min. No metabolism of PLD-118 was detected with rat and dog S9 fractions. A small (8%) decrease in PLD-118 at 100 μM (not detected at 10 μM) with human microsomes was considered to be biologically irrelevant. PLD-118 did not inhibit any of the tested CYPs. PLD-118, at concentrations up to 100 μM, is not metabolized by rat, dog or human liver S9 homogenates and does not inhibit human CYPs in vitro, suggesting little likelihood for interaction of PLD-118 with drugs metabolized by these enzymes. Copyright © 2004 John Wiley & Sons, Ltd.