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.

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Leelamine is a diterpene compound found in the bark of pine trees and has garnered considerable interest owing to its potent anticancer properties. The aim of the present study was to investigate the metabolic profile of leelamine in human liver microsomes (HLMs) and mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We found that leelamine undergoes only Phase I metabolism, which generates one metabolite that is mono-hydroxylated at the C9 carbon of the octahydrophenanthrene ring (M1) both in vitro and in vivo. The structure and metabolic pathway of M1 were determined from the MS fragmentation obtained by collision-induced dissociation using LC-MS/MS in HLMs. Cytochrome p450 (CYP) 2D6 was found to be the dominant CYP enzyme involved in the biotransformation of leelamine to its hydroxylated metabolite, whereas CYP2C19, CYP1A1, and CYP3A4 contributed to some extent. Moreover, we identified only one metabolite M1, in the urine, but none in the feces. In conclusion, leelamine was metabolized to a mono-hydroxyl metabolite by CYP2D6 and mainly excreted in the urine.

Ginseng (Panax ginseng Meyer) is a popular traditional herbal medicine used worldwide. Patients often take ginseng preparations with other medicines where the ginseng dose could exceed the recommended dose during long‐term administration. However, ginseng–drug interactions at high doses of ginseng are poorly understood. This study showed the possibility of herb–drug interactions between the Korean red ginseng (KRG) extract and cytochrome P450 (CYP) substrates in higher administration in mice. The CYP activities were determined in vivo after oral administration of KRG extract doses of 0.5, 1.0, and 2.0 g/kg for 2 or 4 weeks by monitoring the concentration of five CYP substrates/metabolites in the blood. The area under the curve for OH‐midazolam/midazolam catalysed by CYP3A was increased significantly by the administration of 2.0 g/kg KRG extract for 2 and 4 weeks. CYP3A‐catalysed midazolam 1ʹ‐hydroxylation also increased significantly in a dose‐ and time‐dependent manner in the S9 fraction of mouse liver which was not related to induction by transcription. Whereas CYP2D‐catalysed dextromethorphan O‐deethylation decreased in a dose‐ and time‐dependent manner in vivo. In conclusion, interactions were observed between KRG extract and CYP2D and CYP3A substrates at subchronic–high doses of KRG administration in mice.

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Ginseng (Panax ginseng Meyer) has been used as a traditional herbal drug in Asian countries. In this study, herb‐drug interaction (HDI) of Korean red ginseng (KRG) extract was investigated using in vitro and in vivo models. Male 5‐week‐old C54BL/6N mice were administered orally with KRG (0, 0.5, 1, and 2 g/kg) once a day for 2 and 4 weeks. The activities of 5 CYP enzymes were determined by monitoring the concentration of probes in blood by using cocktail assay. CYP2D‐catalyzed dextromethorphan O‐demethylation was found to be significantly induced after repeated administration of KRG. The AUCratio of probe for CYP2D decreased with the elevation of the dose and duration of KRG administration. Contrarily, AUCratio of probe for CYP3A increased on increasing the dose and duration of KRG administration. Similarly, CYP3A‐catalyzed midazolam 1′‐hydroxylation also increased in dose‐dependent manner in vitro. Herein, we suggested the possibility of KRG‐induced drug interaction upon continuous administration for 2 – 4 weeks.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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