Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation.

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Shrestha R, Cho PJ, Paudel S, Shrestha A, Kang MJ, Jeong TC, Lee ES, Lee S

Exploring the Metabolism of Loxoprofen in Liver Microsomes: The Role of Cytochrome P450 and UDP-Glucuronosyltransferase in Its Biotransformation.

Pharmaceutics. 2018 Aug 2;10(3). pii: pharmaceutics10030112. doi: 10.3390/pharmaceutics10030112.

PubMed ID

30072626 [ View in PubMed

]

Abstract

Loxoprofen, a propionic acid derivative, non-steroidal anti-inflammatory drug (NSAID) is a prodrug that is reduced to its active metabolite, trans-alcohol form (Trans-OH) by carbonyl reductase enzyme in the liver. Previous studies demonstrated the hydroxylation and glucuronidation of loxoprofen. However, the specific enzymes catalyzing its metabolism have yet to be identified. In the present study, we investigated metabolic enzymes, such as cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT), which are involved in the metabolism of loxoprofen. Eight microsomal metabolites of loxoprofen were identified, including two alcohol metabolites (M1 and M2), two mono-hydroxylated metabolites (M3 and M4), and four glucuronide conjugates (M5, M6, M7, and M8). Based on the results for the formation of metabolites when incubated in dexamethasone-induced microsomes, incubation with ketoconazole, and human recombinant cDNA-expressed cytochrome P450s, we identified CYP3A4 and CYP3A5 as the major CYP isoforms involved in the hydroxylation of loxoprofen (M3 and M4). Moreover, we identified that UGT2B7 is the major UGT isoform catalyzing the glucuronidation of loxoprofen and its alcoholic metabolites. Further experimental studies should be carried out to determine the potency and toxicity of these identified metabolites of loxoprofen, in order to fully understand of mechanism of loxoprofen toxicity.

DrugBank Data that Cites this Article

Drugs

Loxoprofen

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Loxoprofen	Carbonyl reductase [NADPH] 1	Protein	Humans	No	Substrate	Details
Loxoprofen	Cytochrome P450 3A Subfamily (Protein Group)	Protein group	Humans	Unknown	Substrate	Details
Loxoprofen	UDP-glucuronosyltransferase 2B7	Protein	Humans	Unknown	Substrate	Details

Drug Reactions

Reaction
Loxoprofen DB09212 Carbonyl reductase [NADPH] 1 Loxoprofen trans-OH metabolite DBMET02876	Details
Loxoprofen DB09212 Carbonyl reductase [NADPH] 1 Loxoprofen cis-OH metabolite DBMET02877	Details

Food Interactions

Drug	Interaction
Loxoprofen	Exercise caution with grapefruit products. Loxoprofen is metabolized by CYP3A4 to an inactive metabolite and grapefruit is a CYP3A4 inhibitor.
Loxoprofen	Exercise caution with St. John's Wort. Loxoprofen is metabolized by CYP3A4 to an inactive metabolite and St. Johns Wort is a CYP3A4 inducer.