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The aim of the current study is to identify the human cytochrome P450 (P450) isoforms involved in the two oxidative steps in the bioactivation of clopidogrel to its pharmacologically active metabolite. In the in vitro experiments using cDNA-expressed human P450 isoforms, clopidogrel was metabolized to 2-oxo-clopidogrel, the immediate precursor of its(More)
The aim of this study was to examine the mechanism underlying the elevation in serum creatinine levels caused by a novel des-fluoro(6)-quinolone antibacterial agent, DX-619, in healthy subjects. hOCT2 showed a prominent uptake of creatinine (K(m) = 56.4 mmol/l) among renal organic ion transporters. DX-619 is a potent inhibitor of hOCT2 (K(i) = 0.94(More)
Mechanism-based inhibition of CYP2B6 in human liver microsomes by thienopyridine antiplatelet agents ticlopidine and clopidogrel and the thiolactone metabolites of those two agents plus that of prasugrel were investigated by determining the time- and concentration-dependent inhibition of the activity of bupropion hydroxylase as the typical CYP2B6 activity.(More)
The aim of the current study was to evaluate the accuracy of allometric scaling methods for drugs metabolized by UDP-glucuronosyltransferases (UGTs), such as ketoprofen, imipramine, lorazepam, levofloxacin, zidovudine, diclofenac, furosemide, raloxifene, gemfibrozil, mycophenolic acid, indomethacin, and telmisartan. Human plasma clearance (CL) predictions(More)
Prasugrel and clopidogrel are antiplatelet prodrugs that are converted to their respective active metabolites through thiolactone intermediates. Prasugrel is rapidly hydrolysed by esterases to its thiolactone intermediate, while clopidogrel is oxidized by cytochrome P450 (CYP) isoforms to its thiolactone. The conversion of both thiolactones to the active(More)
Acyl glucuronides (AGs) formed from carboxylic acid-containing drugs have been considered to be a cause of idiosyncratic drug toxicity (IDT). Chemical stability of AGs is supposed to relate to their reactivity. In this study, the half-lives of 21 AGs of carboxylic drugs in potassium phosphate buffer (KPB), human serum albumin (HSA) solution, and human fresh(More)
Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, (14)C-prasugrel or prasugrel was administered to rats at a dose of 5 mg kg(-1). After oral and intravenous dosing, the values of AUC(0-infinity) of total radioactivity were 36.2 and 47.1 microg eqx h ml(-1), respectively. Oral dosing of unlabeled(More)
Ticlopidine, clopidogrel, and prasugrel are thienopyridine prodrugs that inhibit adenosine-5'-diphosphate (ADP)-mediated platelet aggregation in vivo. These compounds are converted to thiol-containing active metabolites through a corresponding thiolactone. The 3 compounds differ in their metabolic pathways to their active metabolites in humans. Whereas(More)
A quantitative method for the determination of clopidogrel active metabolite (AM) in human plasma was developed and validated using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Clopidogrel AM contains a thiol group, thus requiring stabilization in biological samples. The alkylating reagent 2-bromo-3'-methoxyacetophenone was used to stabilize(More)
Interspecies allometric scaling is a useful tool for calculating human pharmacokinetic (PK) parameters from data in animals. In this study, in order to determine the scaling exponent in a simple allometric equation that can predict human clearance (CL) and distribution volume at steady state (Vss) of monoclonal antibodies (mAbs) from monkey data alone, PK(More)