Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol.

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Wu X, Zhang Q, Guo J, Jia Y, Zhang Z, Zhao M, Yang Y, Wang B, Hu J, Sheng L, Li Y

Metabolism of F18, a Derivative of Calanolide A, in Human Liver Microsomes and Cytosol.

Front Pharmacol. 2017 Jul 19;8:479. doi: 10.3389/fphar.2017.00479. eCollection 2017.

PubMed ID

28769808 [ View in PubMed

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Abstract

10-Chloromethyl-11-demethyl-12-oxo-calanolide (F18), an analog of calanolide A, is a novel potent nonnucleoside reverse transcriptase inhibitor against HIV-1. Here, we report the metabolic profile and the results of associated biochemical studies of F18 in vitro and in vivo. The metabolites of F18 were identified based on liquid chromatography-electrospray ionization mass spectrometry and/or nuclear magnetic resonance. Twenty-three metabolites of F18 were observed in liver microsomes in vitro. The metabolism of F18 involved 4-propyl chain oxidation, 10-chloromethyl oxidative dechlorination and 12-carbonyl reduction. Three metabolites (M1, M3-1, and M3-2) were also found in rat blood after oral administration of F18 and the reduction metabolites M3-1 and M3-2 were found to exhibit high potency for the inhibition of HIV-1 in vitro. The oxidative metabolism of F18 was mainly catalyzed by cytochrome P450 3A4 in human microsomes, whereas flavin-containing monooxygenases and 11beta-hydroxysteroid dehydrogenase were found to be involved in its carbonyl reduction. In human cytosol, multiple carbonyl reductases, including aldo-keto reductase 1C, short-chain dehydrogenases/reductases and quinone oxidoreductase 1, were demonstrated to be responsible for F18 carbonyl reduction. In conclusion, the in vitro metabolism of F18 involves multiple drug metabolizing enzymes, and several metabolites exhibited anti-HIV-1 activities. Notably, the described results provide the first demonstration of the capability of FMOs for carbonyl reduction.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Calanolide A	Cytochrome P450 3A4	Protein	Humans	Unknown	Substrate	Details