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The novel antifungal agent PLD‐118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro
Author(s) -
Parnham M.J.,
Bogaards J.J.P.,
Schrander F.,
Schut M.W.,
Orešković K.,
Mildner B.
Publication year - 2005
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.429
Subject(s) - microsome , cyp2e1 , cyp1a2 , cytochrome p450 , cyp3a , cyp2a6 , in vitro , enzyme , biochemistry , cyp3a4 , metabolism , cyp2b6 , biology , unspecific monooxygenase , chemistry , pharmacology
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 µ M ) 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 K m . Incubation mixtures were preincubated with PLD‐118 (0.1–100 µ M ) 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 µ M (not detected at 10 µ M ) 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 µ M , 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.