Shuet-Hing Lee Chiu
Merck & Co.
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Archives of Biochemistry and Biophysics | 1992
Styliani H. Vincent; Bindhu V. Karanam; Susan K. Painter; Shuet-Hing Lee Chiu
The metabolism of the immunosuppressant FK-506 was shown to be catalyzed primarily by cytochrome P450 isozymes of the P450 3A subfamily. Antibodies against rat P450 3A inhibited FK-506 metabolism by 82% in rat liver microsomes and by 35-56% in liver microsomes from humans, dexamethasone-induced rats, and erythromycin-induced rabbits. Poor species cross-reactivity of the antibodies, metabolic switching, and/or some metabolism by P450 isozymes other than P450 3A may be responsible for the incomplete inhibition observed. Besides anti-rat P450 3A, antibodies against rat P450 1A also appeared to have some inhibitory effect implicating these particular cytochrome P450 isozymes as having a minor role in FK-506 metabolism. The formation of 13-desmethyl FK-506, identified here as a major metabolite of FK-506 in all types of microsomes examined, was inhibited completely by anti-P450 3A in liver microsomes from dexamethasone-induced rats and erythromycin-induced rabbits but only partially in human and control rat liver microsomes.
Drug Metabolism and Disposition | 2004
Rosa I. Sanchez; Regina W. Wang; Deborah J. Newton; Ray Bakhtiar; Ping Lu; Shuet-Hing Lee Chiu; David C. Evans; Su-Er W. Huskey
The contribution of human cytochrome P450 (P450) isoforms to the metabolism of aprepitant in humans was investigated using recombinant P450s and inhibition studies. In addition, aprepitant was evaluated as an inhibitor of human P450s. Metabolism of aprepitant by microsomes prepared from baculovirus-expressed human P450s was observed only when CYP1A2, CYP2C19, or CYP3A4 was present in the expression system. Incubation with CYP1A2 and CYP2C19 yielded only products of O-dealkylation, whereas CYP3A4 catalyzed both N- and O-dealkylation reactions. The metabolism of aprepitant by human liver microsomes was inhibited completely by ketoconazole or troleandomycin. No inhibition was observed with other P450 isoform-selective inhibitors. Aprepitant was evaluated also as a P450 inhibitor in human liver microsomes. No significant inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2D6, and CYP2E1 was observed in experiments with isoform-specific substrates (IC50 > 70 μM). Aprepitant was a moderate inhibitor of CYP3A4, with Ki values of ∼10 μM for the 1′- and 4-hydroxylation of midazolam, and the N-demethylation of diltiazem, respectively. Aprepitant was a very weak inhibitor of CYP2C9 and CYP2C19, with Ki values of 108 and 66 μM for the 7-hydroxylation of warfarin and the 4′-hydroxylation of S-mephenytoin, respectively. Collectively, these results indicated that aprepitant is both a substrate and a moderate inhibitor of CYP3A4.
Chemico-Biological Interactions | 1995
Kwan H. Leung; Ming Yao; Ralph A. Stearns; Shuet-Hing Lee Chiu
Studies were undertaken to investigate the mechanism of bioactivation and covalent binding of TNT. Incubation of [14C]TNT with rat liver microsomes in the presence of an NADPH generating system resulted in metabolism and covalent binding to microsomal proteins. Time-dependence studies showed that TNT was rapidly reduced to yield 4-hydroxylamino-2,6-dinitrotoluene (4HA), 4-amino-2,6-dinitrotoluene (4A) and 2-amino-4,6-dinitrotoluene (2A) as intermediates which were further metabolized to form 2,4-diamino-6-nitrotoluene (2,4DA) and 2,6-diamino-4-nitrotoluene (2,6DA). In contrast to the rapid disappearance of TNT, formation of covalent protein adducts increased with time, suggesting that the reactive intermediate was likely to be formed not directly from TNT but from proximal intermediates such as 4HA. The hypothesis that 4HA was more readily converted to the reactive intermediate than TNT was further supported by the increased levels of covalent adduct formation when [14C]4HA was incubated directly with liver microsomes. Covalent binding of TNT and 4HA was dependent on oxygen concentration. Higher levels of covalent adducts were formed when TNT was incubated aerobically (up to 50% oxygen concentration) than under anaerobic conditions. Covalent binding of [14C]4HA also increased with increasing oxygen concentrations. These results suggest that the reactive intermediate is likely to be an oxidized metabolite of 4HA, e.g. 4-nitroso-2,6-dinitrotoluene. Compounds containing a free sulfhydryl group (cysteine, N-acetylcysteine, GSH or 3,4-dichlorobenzenethiol) decreased the amount of covalent binding to various degrees, suggesting the involvement of the sulfhydryl group in adduct formation with TNT following bioactivation. Metabolic activation of TNT by liver microsomes required NADPH but not NADH as the cofactor. Incubation of [14C]TNT with purified rat liver NADPH cytochrome P450 reductase under either aerobic or anaerobic conditions yielded exclusively 4HA. In contrast, 2A and 4A were formed following incubation of TNT with the reconstituted system containing cytochrome P450, NADPH cytochrome P450, reductase and dilauroyl phosphatidylcholine. These observations suggest that the initial reduction of the nitro group can be catalyzed by NADPH cytochrome P450 reductase alone but cytochrome P450 is needed in the reduction of the hydroxylamine to the amine.
Drug Metabolism Reviews | 1987
Shuet-Hing Lee Chiu; Rae Taub; Elena Sestokas; Anthony Y.H. Lu; Theodore A. Jacob
(1987). Comparative in Vivoand in Vitro Metabolism of Ivermectin in Steers, Sheep, Swine, and Rat. Drug Metabolism Reviews: Vol. 18, No. 2-3, pp. 289-302.
Archive | 1989
Shuet-Hing Lee Chiu; Anthony Y.H. Lu
Ivermectin is used widely as an antiparasitic agent in food-producing animals. As in the case of any such drug, the residual tissue concentration of the therapeutic agent, or tissue residue, is a safety concern to the meat-consuming public. To evaluate the toxic potential of the residual tissue concentration of ivermectin and its metabolites, metabolism studies have been carried out in target species (cattle, sheep, swine) using the radiolabeled drug. Comparative metabolic studies were done in a laboratory animal, the rat, and in liver microsomes from various species.
Bioorganic & Medicinal Chemistry Letters | 1999
Thomas L. Shih; Mari R. Candelore; Margaret A. Cascieri; Shuet-Hing Lee Chiu; Lawrence F. Colwell; Liping Deng; William P. Feeney; Michael J. Forrest; Gary J. Hom; D. Euan MacIntyre; Randall R. Miller; Ralph A. Stearns; Catherine D. Strader; Laurie Tota; Matthew J. Wyvratt; Michael H. Fisher; Ann E. Weber
L-770,644 (9c) is a potent and selective agonist of the human beta3 adrenergic receptor (EC50 = 13 nM). It shows good oral bioavailability in both dogs and rats (%F = 27), and is a full agonist for glycerolemia in the rhesus monkey (ED50 = 0.21 mg/kg). Based on its desirable in vitro and in vivo properties, L-770,644 was chosen for further preclinical evaluation.
Chemico-Biological Interactions | 1992
Yu-Ying Liu; Anthony Y.H. Lu; Ralph A. Stearns; Shuet-Hing Lee Chiu
When a single dose of [14C]trinitrotoluene was administered intraperitoneally (i.p.) to rats at 1, 10 or 50 mg/kg of body weight, covalently bound radioactivity was detected in globin, plasma proteins and proteins in the liver and kidney. The extent of covalent binding was dose dependent and was highest in plasma and renal proteins at all times up to 4 h after dosing. Covalent adduct levels in globin, however, decline slower than others. At a dose of 50 mg/kg of body weight, globin covalent adduct levels peaked at 1 h after dosing at 182 pmol/mg protein and subsequently decreased to approximately 50 pmol/mg protein between days 1 and 8. Of the covalent adduct levels in liver and kidney, those in the 10,000 x g and microsomal fractions were found to be higher than that in the cytosolic fraction. Radioactivity covalently bound to globin and the hepatic proteins was susceptible to dilute acid hydrolysis from which 2-amino-4,6-dinitrotoluene (2A) and 4-amino 2,6-dinitrotoluene (4A) were the major products recovered by solvent extraction. Upon acetylation, the hydrolysate gave rise to derivatives identified as the acetates of 2A and 4A on the basis of mass spectrometry and HPLC cochromatography with authentic samples. Four hours after an i.p. dose of [14C]TNT at 50 mg/kg of body weight about 0.4% of the dose was found as bound adducts to hemoglobin, of which approximately 48% was recovered as solvent extractable radioactivity after acid hydrolysis. About 2% of the radioactive dose was in the liver, of which approximately 30% was covalently bound to hepatic proteins, and approximately 49% of that was convertible to solvent extractable radioactivity upon acid hydrolysis. In vitro incubation of [14C]TNT with blood showed that there was a linear increase of covalent adducts in globin during the first 2 h of incubation; the concentration of covalent adducts was slightly higher than that with plasma proteins. The major compounds recovered from the hydrolysate of the globin adducts were also 2A and 4A as obtained from globin in the in vivo studies. On the basis of the in vitro and in vivo study results, we have confirmed the formation of protein adducts following a single i.p. administration of [14C]TNT at 1, 10 or 50 mg/kg of body weight to the rat or by in vitro incubation with blood.(ABSTRACT TRUNCATED AT 400 WORDS)
Bioorganic & Medicinal Chemistry Letters | 1998
Ann E. Weber; Hyun O. Ok; Raul F. Alvaro; Mari R. Candelore; Margaret A. Cascieri; Shuet-Hing Lee Chiu; Liping Deng; Michael J. Forrest; Gary J. Hom; Jennifer E. Hutchins; John Kao; D. Euan MacIntyre; Robert J. Mathvink; Debra McLoughlin; Randall R. Miller; Ronald C. Newbold; Timothy V. Olah; Emma R. Parmee; Leroy Perkins; Ralph A. Stearns; Catherine D. Strader; John Szumiloski; Yui S. Tang; Laurie Tota; Pasquale P. Vicario; Matthew J. Wyvratt; Michael H. Fisher
Pyridyloxypropanolamines L-749,372 (8, beta 3 EC50 = 3.6 nM) and L-750,355 (29, beta 3 EC50 = 13 nM) are selective partial agonists of the human receptor, with 33% and 49% activation, respectively. Both stimulate lipolysis in rhesus monkeys (ED50 = 2 and 0.8 mg/kg, respectively), with minimal effects on heart rate. Oral bioavailability in dogs, 41% for L-749,372 and 47% for L-750,355, is improved relative to phenol analogs.
Journal of Pharmacological and Toxicological Methods | 1993
Shuet-Hing Lee Chiu
In vitro models derived from various animal species are routinely used for the evaluation of pharmacological potency and toxicological potential of new drug candidates. It is well known that metabolism of the drug molecule often contributes to the efficacy and toxicity observed in vivo. In vitro metabolism studies conducted in biological matrixes ranging from intact organ, tissue slice to subcellular fraction offer the advantage of reduced complexity of the study system, and allow the evaluation of intrinsic metabolic potential or mechanism with respect to a specific reaction. In addition, in vitro systems derived from various animal species offer the possibility of comparing metabolic pathways among species, including humans, before a compound can be tested clinically. Two areas of particular interest for the use of in vitro studies in the understanding of new drugs are 1) the relationship of metabolic pathway and pharmacodynamics and 2) the prediction of drug interaction potential in humans. To illustrate these aspects, I review metabolism studies on losartan, an angiotensin-II receptor antagonist currently in phase-III clinical development for hypertension, and cyclosporin A, a widely prescribed immunosuppressant.
Bioorganic & Medicinal Chemistry Letters | 1997
James R. Tata; Zhijian Lu; Thomas M. Jacks; Klaus D. Schleim; Kang Cheng; Liente Wei; Wanda W.-S. Chan; Bridget Butler; Nancy N. Tsou; Kwan Leung; Shuet-Hing Lee Chiu; Gerard J. Hickey; Roy G. Smith; Arthur A. Patchett
The design, synthesis, and activities of a series of short duration spiroindane growth hormone secretagogues are reported. Incorporation of a readily metabolized ester into the spiroindane benzylic position provided a series of highly potent orally active secretagogues with a short duration of action.