Buprenorphine (BUP) is a synthetic derivative of the morphine alkaloid thebaine. BUP is metabolized by N-dealkylation to form the active metabolite nor-buprenorphine (Nor-BUP), and both undergo subsequent glucuronidation. Although BUP has been used clinically for years, its metabolism has still not been fully elucidated. The aim of this study was to clarify the identity of the human hepatic cyt...

We developed 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl} propionic acid (T-5224) as a novel inhibitor of the c-Fos/activator protein-1 for rheumatoid arthritis therapy. We predicted the metabolism of T-5224 in humans by using human liver microsomes (HLM), human intestinal microsomes (HIM), recombinant human cytochrome P450 (P450), and UDP-glucu...

Nano-sized particles are known to interfere with drug-metabolizing cytochrome P450 (CYP) enzymes, which can be anticipated to be a potential source of unintended adverse reactions, but the mechanisms underlying the inhibition are still not well understood. Herein we report a systematic investigation of the impacts of gold nanoparticles (AuNPs) on five major CYP isozymes under in vitro incubatio...

Previous studies in our laboratory showed that among cDNA-expressed human cytochrome P450 (P450) supersomes, CYP2C19 was the most active in methoxychlor-O-demethylation. However, based on the lack of inhibition of methoxychlor-O-demethylation by monoclonal anti-CYP2C19 antibodies in human liver microsomes (HLM), CYP2C19 did not seem to catalyze that reaction in HLM. By contrast, CYP2C9, much le...

AIMS The objective of this study was to evaluate the potential uses of relative abundance, relative activity approaches and inhibitory monoclonal antibodies (mAbs) in the characterization of CYP enzymology in early drug discovery. METHODS Intrinsic clearance estimates for the oxidation of ethoxyresorufin (a selective probe of CYP1A2 activity), tolbutamide (CYP2C9), S-mephenytoin (CYPC19), dex...

This study aimed to establish a practical and simplified method of predicting intestinal availability in humans (F(g,human)) at the drug discovery stage using in vitro metabolic clearance values and permeability clearance values. A prediction model for F(g,human) of 19 CYP3A substrates and 5 UGT substrates was constructed based on the concept that the permeability clearance values mean the perm...

Wushanicaritin, a natural polyphenol compound, exerts many biological activities. This study aimed to characterize wushanicaritin glucuronidation by pooled human liver microsomes (HLM), human intestine microsomes and individual uridine diphosphate-glucuronosyltransferase (UGT) enzyme. Glucuronidation rates were determined by incubating wushanicaritin with uridine diphosphoglucuronic acid-supple...

Desloratadine (Clarinex), the major active metabolite of loratadine (Claritin), is a nonsedating antihistamine used for the treatment of seasonal allergies and hives. Previously we reported that the formation of 3-hydroxydesloratadine, the major human metabolite of desloratadine, involves three sequential reactions, namely N-glucuronidation by UGT2B10 followed by 3-hydroxylation by CYP2C8 follo...

In this study we have evaluated the application and reliability of using fluorescence (FLUO)-based high throughput screening assays with recombinant CYPs (rCYP). This was accomplished by screening 29 clinically important antiparasitic drugs for inhibition of the five major drug-metabolizing CYPs (-1A2, -2C9, -2C19, -2D6, and -3A4). Data from FLUO/rCYP assays were compared with that obtained by ...

BACKGROUND: Cranberry products have been implicated in several case reports to enhance the anticoagulant effect of warfarin. The mechanism could involve inhibition of the hepatic CYP2C9-mediated metabolic clearance of warfarin by components in cranberry. Because dietary/natural substances vary substantially in bioactive ingredient composition, multiple cranberry products were evaluated in vitro...