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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 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)
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)
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)
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)
Cerebral amyloid-beta peptide (Abeta) clearance plays a key role in determining the brain level of Abeta; however, its mechanism remains unclear. In this study, we investigated cerebral Abeta clearance across the blood-brain barrier (BBB) by using the Brain Efflux Index method. [125I]Abeta(1-40) was eliminated from rat brain to circulating blood with a(More)
We investigated the inhibitory effects of the angiotensin receptor blockers (ARBs), candesartan, irbesartan, losartan, losartan active metabolite (EXP-3174), olmesartan, telmisartan and valsartan (0.3-300 microM), on the CYP2C9 activity in human liver microsomes using (S)-(-)-warfarin as a typical CYP2C9 substrate. Except for olmesartan and valsartan, these(More)
We have previously reported that human total body clearance (CL) and steady-state volume of distribution (Vss) of monoclonal antibodies (mAbs) could be predicted reasonably well from monkey data alone using simple allometry with scaling exponents of 0.79 and 1.12 (for soluble targets), and 0.96 and 1.00 (for membrane-bound targets). In the present study, to(More)
Mechanism-based inhibition of CYP2C19 in human liver microsomes by the thienopyridine antiplatelet agents clopidogrel, prasugrel and their thiolactone metabolites was investigated by determining the time- and concentration-dependent inhibition of the activity of S-mephenytoin 4'-hydroxylase as typical CYP2C19 activity and compared with ticlopidine and its(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)