The novel antifungal agent PLD-118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro
article
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.
Topics
Physiological SciencesCytochrome P450MetabolismPLD-1182 amino 4 methylenecyclopentanecarboxylic acidAlpha naphthoflavoneAmino acidAntifungal agentBufuralolChlorzoxazoneCoumarinCytochrome P450Cytochrome P450 1A2Cytochrome P450 2A6Cytochrome P450 2B6Cytochrome P450 2C19Cytochrome P450 2C9Cytochrome P450 2D6Cytochrome P450 2E1Cytochrome P450 3ADiclofenacDiethyldithiocarbamic acidEthoxyresorufinKetoconazoleMephenytoinMonoclonal antibodyMonoclonal antibody 2B6QuinidineReduced nicotinamide adenine dinucleotide phosphateResorufinSulfaphenazoleTestosteroneUmbelliferoneUnclassified drugUnindexed drugAnalytic methodAnimal tissueCandidiasisConcentration responseControlled studyDerivatizationDogDrug structureEnzyme assayEnzyme inhibitionEnzyme stabilityEnzyme substrateFluorescence analysisHigh performance liquid chromatographyHumanHuman tissueIn vitro studyLiver homogenateLiver microsome metabolismNonhumanRatStructure analysisAdministration, OralAnimalsAntifungal AgentsChemistry, PharmaceuticalCycloleucineCytochrome P-450 Enzyme SystemDogsDrug Evaluation, PreclinicalHumansMicrosomes, LiverRatsRibosomal Proteins
TNO Identifier
238297
ISSN
01422782
Source
Biopharmaceutics and Drug Disposition, 26(1), pp. 27-33.
Pages
27-33
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