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154 results on '"Farid, Nagy"'

6. Effects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel

Author

Small, David S., Farid, Nagy A., Payne, Christopher D., Weerakkody, Govinda J., Li, Ying G., Brandt, John T., Salazar, Daniel E., and Winters, Kenneth J.

Subjects
Eli Lilly and Co., Lilly Research Laboratories, Health maintenance organizations, Lansoprazole -- Dosage and administration, Metabolites, Drug interactions -- Dosage and administration, Blood platelets -- Aggregation, Pharmaceutical industry, Health, Dosage and administration
Abstract

Keywords: Clopidogrel; prasugrel; lansoprazole; drug interaction 475 Drug InteractionsEffects of the Proton Pump Inhibitor Lansoprazole on the Pharmacokinetics and Pharmacodynamics of Prasugrel and Clopidogrel SAGE Publications, Inc.200810.1177/0091270008315310 David S.Small PhD [...]

Published
2008
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7. Prasugrel, a New Thienopyridine Antiplatelet Drug, Weakly Inhibits Cytochrome P450 2B6 in Humans

Author

Farid, Nagy A., Payne, Christopher D., Ernest, C. Steven, Li, Y. Grace, Winters, Kenneth J., Salazar, Daniel E., and Small, David S.

Subjects
Prodrugs -- Dosage and administration -- Research, Cytochrome P-450 -- Health aspects -- Research, Blood platelets -- Aggregation, Health, Research, Dosage and administration, Health aspects
Abstract

Keywords: Bupropion; CYP2B6 inhibition; hydroxybupropion; prasugrel; thienopyridines; drug interactions 53 Drug InteractionsPrasugrel, a New Thienopyridine Antiplatelet Drug, Weakly Inhibits Cytochrome P450 2B6 in Humans SAGE Publications, Inc.200810.1177/0091270007309709 Nagy A.Farid PhD [...]

Published
2008
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17. Relationship between protein kinase C and ATPases

Author

Kowluru, Renu A., Jirousek, Michael R., Stramm, Lawrence, Farid, Nagy, Engerman, Ronald L., and Kern, Timothy S.

Subjects
Diabetic retinopathy -- Physiological aspects, Adenosine triphosphatase -- Physiological aspects, Protein kinases -- Physiological aspects, Health, Physiological aspects
Abstract

In the retinas of diabetic animals, protein kinase C (PKC) activity is elevated, and [Na.sup.+]-[K.sup.+]-ATPase and calcium ATPase activities are subnormal. These abnormalities are also present in another model of [...]

Published
1998

19. Pharmacokinetics and pharmacodynamics following maintenance doses of prasugrel and clopidogrel in Chinese carriers of CYP2C19 variants

Author

Kelly, Ronan P, Close, Sandra L, Farid, Nagy A, Winters, Kenneth J, Shen, Lei, Natanegara, Fanni, Jakubowski, Joseph A, Ho, Mary, Walker, Joseph R, and Small, David S

Subjects
Adult, Blood Platelets, Male, Cross-Over Studies, Polymorphism, Genetic, Ticlopidine, Dose-Response Relationship, Drug, Platelet Aggregation, Pharmacokinetic Dynamic Relationships, Thiophenes, Piperazines, Clopidogrel, Pedigree, Cytochrome P-450 CYP2C19, Young Adult, Purinergic P2Y Receptor Antagonists, Humans, Drug Interactions, Female, Aryl Hydrocarbon Hydroxylases, Prasugrel Hydrochloride, Platelet Aggregation Inhibitors
Abstract

This open-label, two-period, randomized, crossover study was designed to determine the effect of CYP2C19 reduced function variants on exposure to active metabolites of, and platelet response to, prasugrel and clopidogrel.Ninety healthy Chinese subjects, stratified by CYP2C19 phenotype, were randomly assigned to treatment with prasugrel 10 mg or clopidogrel 75 mg for 10 days followed by 14 day washout and 10 day treatment with the other drug. Eighty-three subjects completed both treatment periods. Blood samples were collected at specified time points for measurement of each drug's active metabolite (Pras-AM and Clop-AM) concentrations and determination of inhibition of platelet aggregation (IPA) by light transmittance aggregometry. CYP2C19 genotypes were classified into three predicted phenotype groups: rapid metabolizers [RMs (*1/*1)], heterozygous or intermediate metabolizers [IMs (*1/*2, *1/*3)] and poor metabolizers [PMs (*2/*2, *2/*3)].Pras-AM exposure was similar in IMs and RMs (90% CI 0.85, 1.03) and slightly lower in PMs than IMs (90% CI 0.74, 0.99), whereas Clop-AM exposure was significantly lower in IMs compared with RMs (90% CI 0.62, 0.83), and in PMs compared with IMs (90% CI 0.53, 0.82). IPA was more consistent among RMs, IMs and PMs in prasugrel treated subjects (80.2%, 84.2% and 80.2%, respectively) than in clopidogrel treated subjects (59.7%, 56.2% and 36.8%, respectively; P0.001).Prasugrel demonstrated higher active metabolite exposure and more consistent pharmacodynamic response across all three predicted phenotype groups compared with clopidogrel, confirming observations from previous research that CYP2C19 phenotype plays an important role in variability of response to clopidogrel, but has no impact on response to prasugrel.

Published
2012

22. The pharmacokinetics and pharmacodynamics of prasugrel in healthy Chinese, Japanese, and Korean subjects compared with healthy Caucasian subjects

Author

Small, David S., primary, Kothare, Prajakti, additional, Yuen, Eunice, additional, Lachno, D. Richard, additional, Li, Ying G., additional, Winters, Kenneth J., additional, Farid, Nagy A., additional, Ni, Lan, additional, Jakubowski, Joseph A., additional, Salazar, Daniel E., additional, Thieu, Vivian T., additional, and Payne, Christopher D., additional

Published
2009
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38. Determination of the active and inactive metabolites of prasugrel in human plasma by liquid chromatography/tandem mass spectrometry

Author

Farid, Nagy A., primary, McIntosh, Mary, additional, Garofolo, Fabio, additional, Wong, Ernest, additional, Shwajch, Amanda, additional, Kennedy, Monika, additional, Young, Michelle, additional, Sarkar, Pratibha, additional, Kawabata, Kiyoshi, additional, Takahashi, Makoto, additional, and Pang, Henrianna, additional

Published
2006
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39. Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure

Author

Abraham, Edward, primary, Naum, Chris, additional, Bandi, Venkata, additional, Gervich, Daniel, additional, Lowry, Stephen F., additional, Wunderink, Richard, additional, Schein, Roland M., additional, Macias, William, additional, Skerjanec, Simona, additional, Dmitrienko, Alex, additional, Farid, Nagy, additional, Forgue, S. Thomas, additional, and Jiang, Frank, additional

Published
2003
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44. Single-Dose and Steady-State Pharmacokinetics of Tomoxetine in Normal Subjects.

Author

Farid, Nagy A., Bergstrom, Richard F., Ziege, Edgar A., Parli, C. John, and Lemberger, Louis

Abstract

A pharmacokinetic profile of tomoxetine, a selective norepinephrine uptake inhibitor, was developed in human volunteers following single and multiple oral administrations. Following the administration of a single 90-mg oral dose of tomoxetine to four normal volunteers, the plasma half-life was 4.3 ± 0.5 hours. Mean plasma clearance was 0.60 ± 0.14 L/Kg/hr, and the mean volume of distribution was 3.7 4pL 0.9 L/kg. Multiple doses of tomoxetine (20 mg bid and 40 mg bid) for seven days were administered to an additional seven subjects. The data appeared to have a bimodal distribution. The mean plasma half-life determined following the last dose was 4.6 ± 0.5 hours in five subjects. The other two subjects, one at each dose level, demonstrated accumulation of tomoxetine occurring from the first to last dose where tomoxetine disappeared from plasma with a mean half-life of 19 hours. [ABSTRACT FROM AUTHOR]

Published
1985
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45. Identification of the Human Cytochrome P450 Enzymes Involved in the Two Oxidative Steps in the Bioactivation of Clopidogrel to Its Pharmacologically Active Metabolite

Author

Kazui, Miho, Nishiya, Yumi, Ishizuka, Tomoko, Hagihara, Katsunobu, Farid, Nagy A., Okazaki, Osamu, Ikeda, Toshihiko, and Kurihara, Atsushi

Abstract

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 pharmacologically active metabolite. CYP1A2, CYP2B6, and CYP2C19 catalyzed this reaction. In the same system using 2-oxo-clopidogrel as the substrate, detection of the active metabolite of clopidogrel required the addition of glutathione to the system. CYP2B6, CYP2C9, CYP2C19, and CYP3A4 contributed to the production of the active metabolite. Secondly, the contribution of each P450 involved in both oxidative steps was estimated by using enzyme kinetic parameters. The contribution of CYP1A2, CYP2B6, and CYP2C19 to the formation of 2-oxo-clopidogrel was 35.8, 19.4, and 44.9%, respectively. The contribution of CYP2B6, CYP2C9, CYP2C19, and CYP3A4 to the formation of the active metabolite was 32.9, 6.76, 20.6, and 39.8%, respectively. In the inhibition studies with antibodies and selective chemical inhibitors to P450s, the outcomes obtained by inhibition studies were consistent with the results of P450 contributions in each oxidative step. These studies showed that CYP2C19 contributed substantially to both oxidative steps required in the formation of clopidogrel active metabolite and that CYP3A4 contributed substantially to the second oxidative step. These results help explain the role of genetic polymorphism of CYP2C19 and also the effect of potent CYP3A inhibitors on the pharmacokinetics and pharmacodynamics of clopidogrel in humans and on clinical outcomes.

Published
2010

46. Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel

Author

Nishiya, Yumi, Hagihara, Katsunobu, Ito, Takashi, Tajima, Masami, Miura, Shin-ichi, Kurihara, Atsushi, Farid, Nagy A., and Ikeda, Toshihiko

Abstract

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. By comparing the ratios of kinact(maximal inactivation rate constant)/KI(the inactivator concentration producing a half-maximal rate of inactivation), it was found that the thiolactone metabolite of prasugrel is 10- and 22-fold less potent, respectively, in the mechanism-based inhibition of CYP2B6 than ticlopidine and clopidogrel. The kinact/KIratio of the thiolactone metabolite of ticlopidine was comparable with that of the parent compound, whereas this ratio for the thiolactone metabolite of clopidogrel was significantly smaller than that of clopidogrel. In conclusion, ticlopidine, its thiolactone metabolite, and clopidogrel were more potent mechanism-based inhibitors of CYP2B6 than the thiolactone metabolite of prasugrel.

Published
2009

47. The Biotransformation of Prasugrel, a New Thienopyridine Prodrug, by the Human Carboxylesterases 1 and 2

Author

Williams, Eric T., Jones, Karen O., Ponsler, G. Douglas, Lowery, Shane M., Perkins, Everett J., Wrighton, Steven A., Ruterbories, Kenneth J., Kazui, Miho, and Farid, Nagy A.

Abstract

2-Acetoxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (prasugrel) is a novel thienopyridine prodrug with demonstrated inhibition of platelet aggregation and activation. The biotransformation of prasugrel to its active metabolite, 2-[1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-mercapto-3-piperidinylidene]acetic acid (R-138727), requires ester bond hydrolysis, forming the thiolactone 2-[2-oxo-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]-1-cyclopropyl-2-(2-fluorophenyl)ethanone(R-95913), followed by cytochrome P450–mediated metabolism to the active metabolite. The presumed role of the human liver- and intestinal-dominant carboxylesterases, hCE1 and hCE2, respectively, in the conversion of prasugrel to R-95913 was determined using expressed and purified enzymes. The hydrolysis of prasugrel is at least 25 times greater with hCE2 than hCE1. Hydrolysis of prasugrel by hCE1 showed Michaelis-Menten kinetics yielding an apparent Kmof 9.25 µM and an apparent Vmaxof 0.725 nmol product/min/µg protein. Hydrolysis of prasugrel by hCE2 showed a mixture of Hill kinetics at low substrate concentrations and substrate inhibition at high concentrations. At low concentrations, prasugrel hydrolysis by hCE2 yielded an apparent Ksof 11.1 µM, an apparent Vmaxof 19.0 nmol/min/µg, and an apparent Hill coefficient of 1.42, whereas at high concentrations, an apparent IC50of 76.5 µM was obtained. In humans, no in vivo evidence of inhibition exists. In vitro transport studies using the intestinal Caco-2 epithelial cell model showed a high in vivo absorption potential for prasugrel and rapid conversion to R-95913. In conclusion, the human carboxylesterases efficiently mediate the conversion of prasugrel to R-95913. These data help explain the rapid appearance of R-138727 in human plasma, where maximum concentrations are observed 0.5 h after a prasugrel p.o. dose, and the rapid onset of action of prasugrel.

Published
2008

50. Fluorescamine Use in High-Performance Liquid Chromatographic Determination of Aminocaproic Acid in Serum

Author

Farid, Nagy A.

Abstract

A sensitive and specific high-performance liquid chromatographic determination of aminocaproic acid in serum is described. ω-Aminocaprylic acid is used as an internal standard. To 10μl of serum, 10μl of the internal standard solution and 50μl of ethanol are added. After centrifugation, a portion of the supernate is evaporated. The residue is dissolved in 750μl of 50mMdibasic sodium phosphate, and then 250μl of fluorescamine in acetonitrile (35mg/100ml) is added. The reaction mixture is chromatographed using a column of octadecylsilane bonded to silica and 44% acetonitrile in 0.5mMphosphoric acid as the eluent. Quantitation is achieved by monitoring either the absorbance of the effluent at 405nm or the fluorescence of the compounds with a fluorometer equipped with a flowcell. The method is reproducible, simple, and fast and has a precision of 4.4%.

Published
1979
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