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Ticlopidine as a Selective Mechanism-Based Inhibitor of Human Cytochrome P450 2C19

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Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris V, 45 Rue des Saints-Pères, 75270 Paris Cedex 06, France, and National Institutes of Health, NIEHS, Research Triangle Park, North Carolina 27709
Cite this: Biochemistry 2001, 40, 40, 12112–12122
Publication Date (Web):September 15, 2001
https://doi.org/10.1021/bi010254c
Copyright © 2001 American Chemical Society

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    Abstract

    Experiments using recombinant yeast-expressed human liver cytochromes P450 confirmed previous literature data indicating that ticlopidine is an inhibitor of CYP 2C19. The present studies demonstrated that ticlopidine is selective for CYP 2C19 within the CYP 2C subfamily. UV−visible studies on the interaction of a series of ticlopidine derivatives with CYP 2C19 showed that ticlopidine binds to the CYP 2C19 active site with a Ks value of 2.8 ± 1 μM. Derivatives that do not involve either the o-chlorophenyl substituent, the free tertiary amine function, or the thiophene ring of ticlopidine did not lead to such spectral interactions and failed to inhibit CYP 2C19. Ticlopidine is oxidized by CYP 2C19 with formation of two major metabolites, the keto tautomer of 2-hydroxyticlopidine (1) and the dimers of ticlopidine S-oxide (TSOD) (Vmax = 13 ± 2 and 0.4 ± 0.1 min-1). During this oxidation, CYP 2C19 was inactivated; the rate of its inactivation was time and ticlopidine concentration dependent. This process meets the chemical and kinetic criteria generally accepted for mechanism-based enzyme inactivation. It occurs in parralel with CYP 2C19-catalyzed oxidation of ticlopidine, is inhibited by an alternative well-known substrate of CYP 2C19, omeprazole, and correlates with the covalent binding of ticlopidine metabolite(s) to proteins. Moreover, CYP 2C19 inactivation is not inhibited by the presence of 5 mM glutathione, suggesting that it is due to an alkylation occurring inside the CYP 2C19 active site. The effects of ticlopidine on CYP 2C19 are very analogous with those previously described for the inactivation of CYP 2C9 by tienilic acid. This suggests that a similar electrophilic intermediate, possibly a thiophene S-oxide, is involved in the inactivation of CYP 2C19 and CYP 2C9 by ticlopidine and tienilic acid, respectively. The kinetic parameters calculated for ticlopidine-dependent inactivation of CYP 2C19, i.e., t1/2max = 3.4 min, kinact = 3.2 10-3 s-1, KI = 87 μM, kinact/KI = 37 L·mol-1·s-1, and r (partition ratio) = 26 (in relation with formation of 1 + TSOD), classify ticlopidine as an efficient mechanism-based inhibitor although somewhat less efficient than tienilic acid for CYP 2C9. Importantly, ticlopidine is the first selective mechanism-based inhibitor of human liver CYP 2C19 and should be a new interesting tool for studying the topology of the active site of CYP 2C19.

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     This work was funded in part by a grant from the European Community (BIOMED2; BMH4 CTD6 0658).

     Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS.

    §

     National Institutes of Health.

    *

     To whom correspondence should be addressed. Fax:  33-1-42 86 83 87. E-mail:  [email protected].

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    12. Prasad V. Bharatam, Omkar R. Valanju, Aabid A. Wani, Devendra K. Dhaked. Importance of tautomerism in drugs. Drug Discovery Today 2023, 28 (4) , 103494. https://doi.org/10.1016/j.drudis.2023.103494
    13. So Shinya, Yusuke Kawai, Mitsuki Kondo, Shouta M.M. Nakayama, Mayumi Ishizuka, Yoshinori Ikenaka. Characteristics of cytochrome P450-dependent metabolism against acetamiprid in the musk shrew (Suncus murinus). Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology 2023, 265 , 109537. https://doi.org/10.1016/j.cbpc.2022.109537
    14. Yoshiya Yamamura, Kouichi Yoshinari, Yasushi Yamazoe. Construction of a fused grid-based CYP2C19-Template system and the application. Drug Metabolism and Pharmacokinetics 2023, 48 , 100481. https://doi.org/10.1016/j.dmpk.2022.100481
    15. DAN A. ROCK, LARRY C. WIENKERS. Characterization of Cytochrome P450 Mechanism Based Inhibition. 2022, 465-526. https://doi.org/10.1002/9781119851042.ch15
    16. Derek R. Boyd, Narain D. Sharma, Paul J. Stevenson, Patrick Hoering, Christopher C. R. Allen, Patrick M. Dansette. Monooxygenase- and Dioxygenase-Catalyzed Oxidative Dearomatization of Thiophenes by Sulfoxidation, cis-Dihydroxylation and Epoxidation. International Journal of Molecular Sciences 2022, 23 (2) , 909. https://doi.org/10.3390/ijms23020909
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    19. Muhammad Faisal, Quret ul Aein, Aamer Saeed, Amara Mumtaz, Fayaz Ali Larik. Highly productive and scalable approach to synthesize ticlopidine: A potent thienopyridine anti-platelet aggregation drug. Heliyon 2020, 6 (12) , e05731. https://doi.org/10.1016/j.heliyon.2020.e05731
    20. Jukka Hakkola, Janne Hukkanen, Miia Turpeinen, Olavi Pelkonen. Inhibition and induction of CYP enzymes in humans: an update. Archives of Toxicology 2020, 94 (11) , 3671-3722. https://doi.org/10.1007/s00204-020-02936-7
    21. Chaitanya K. Jaladanki, Anuj Gahlawat, Gajanan Rathod, Hardeep Sandhu, Kousar Jahan, Prasad V. Bharatam. Mechanistic studies on the drug metabolism and toxicity originating from cytochromes P450. Drug Metabolism Reviews 2020, 52 (3) , 366-394. https://doi.org/10.1080/03602532.2020.1765792
    22. Jaydeep Yadav, Erickson Paragas, Ken Korzekwa, Swati Nagar. Time-dependent enzyme inactivation: Numerical analyses of in vitro data and prediction of drug-drug interactions. Pharmacology & Therapeutics 2020, 206 , 107449. https://doi.org/10.1016/j.pharmthera.2019.107449
    23. Everaldo F. Krake, Wolfgang Baumann. Unprecedented Formation of 2‐Chloro‐5‐(2‐chlorobenzyl)‐4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine 5‐oxide via Oxidation‐Chlorination Reaction Using Oxone: A Combination of Synthesis and 1D‐2D NMR Studies. ChemistrySelect 2019, 4 (46) , 13479-13484. https://doi.org/10.1002/slct.201903556
    24. Thies Thiemann. Thiophene S-Oxides. 2019https://doi.org/10.5772/intechopen.79080
    25. Yashpal S. Chhonker, Hardik Chandasana, Veenu Bala, Rao Mukkavilli, Deepak Kumar, Subrahmanyam Vangala, Rabi S. Bhatta. In-vitro metabolism, CYP profiling and metabolite identification of E- and Z- guggulsterone, a potent hypolipidmic agent. Journal of Pharmaceutical and Biomedical Analysis 2018, 160 , 202-211. https://doi.org/10.1016/j.jpba.2018.06.047
    26. Muhammad W. Ashraf, Marko A. Peltoniemi, Klaus T. Olkkola, Pertti J. Neuvonen, Teijo I. Saari. Semimechanistic Population Pharmacokinetic Model to Predict the Drug–Drug Interaction Between S ‐ketamine and Ticlopidine in Healthy Human Volunteers. CPT: Pharmacometrics & Systems Pharmacology 2018, 7 (10) , 687-697. https://doi.org/10.1002/psp4.12346
    27. Kathryn Elisa Burns, Phillip Shepherd, Graeme Finlay, Malcolm Drummond Tingle, Nuala Ann Helsby. Indirect regulation of CYP2C19 gene expression via DNA methylation. Xenobiotica 2018, 48 (8) , 781-792. https://doi.org/10.1080/00498254.2017.1372648
    28. James C. Waddington, Xiaoli Meng, Dean J. Naisbitt, B. Kevin Park. Immune drug-induced liver disease and drugs. Current Opinion in Toxicology 2018, 10 , 46-53. https://doi.org/10.1016/j.cotox.2017.12.006
    29. Tae Kong, Soon-Sang Kwon, Jae Cheong, Hee Kim, Jin Kim, Hye Lee. In Vitro Inhibitory Effects of Synthetic Cannabinoid EAM-2201 on Cytochrome P450 and UDP-Glucuronosyltransferase Enzyme Activities in Human Liver Microsomes. Molecules 2018, 23 (4) , 920. https://doi.org/10.3390/molecules23040920
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    31. Daisuke Satoh, Satoru Iwado, Satoshi Abe, Kanako Kazuki, Shinobu Wakuri, Mitsuo Oshimura, Yasuhiro Kazuki, . Establishment of a novel hepatocyte model that expresses four cytochrome P450 genes stably via mammalian-derived artificial chromosome for pharmacokinetics and toxicity studies. PLOS ONE 2017, 12 (10) , e0187072. https://doi.org/10.1371/journal.pone.0187072
    32. Jasleen Sodhi, Erlie Delarosa, Jason Halladay, James Driscoll, Teresa Mulder, Patrick Dansette, S. Khojasteh. Inhibitory Effects of Trapping Agents of Sulfur Drug Reactive Intermediates against Major Human Cytochrome P450 Isoforms. International Journal of Molecular Sciences 2017, 18 (7) , 1553. https://doi.org/10.3390/ijms18071553
    33. Matthew Y. Bendikov, John O. Miners, Bradley S. Simpson, David J. Elliot, Susan J. Semple, David J. Claudie, Ross A. McKinnon, Elizabeth M. J. Gillam, Matthew J. Sykes. In vitro metabolism of the anti-inflammatory clerodane diterpenoid polyandric acid A and its hydrolysis product by human liver microsomes and recombinant cytochrome P450 and UDP-glucuronosyltransferase enzymes. Xenobiotica 2017, 47 (6) , 461-469. https://doi.org/10.1080/00498254.2016.1203041
    34. Lisa Gross, Dániel Aradi, Dirk Sibbing. Pharmacology: Inhibitors of P2Y12. 2017, 1253-1267. https://doi.org/10.1007/978-3-319-47462-5_84
    35. J. E. Sager, L. S. L. Price, N. Isoherranen. Stereoselective Metabolism of Bupropion to OH-bupropion, Threohydrobupropion, Erythrohydrobupropion, and 4'-OH-bupropion in vitro. Drug Metabolism and Disposition 2016, 44 (10) , 1709-1719. https://doi.org/10.1124/dmd.116.072363
    36. . Substrates of Human CYP2D6. 2016, 139-288. https://doi.org/10.1201/b19643-4
    37. Mahendra Kumar Hidau, Yeshwant Singh, Shio Kumar Singh. Determination of metabolic profile of novel triethylamine containing thiophene S006‐830 in rat, rabbit, dog and human liver microsomes. Drug Testing and Analysis 2016, 8 (2) , 180-188. https://doi.org/10.1002/dta.1802
    38. Janne T. Backman, Anne M. Filppula, Mikko Niemi, Pertti J. Neuvonen, . Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions. Pharmacological Reviews 2016, 68 (1) , 168-241. https://doi.org/10.1124/pr.115.011411
    39. Jayaprakasam Bolleddula, Swapan K. Chowdhury. Carbon–carbon bond cleavage and formation reactions in drug metabolism and the role of metabolic enzymes. Drug Metabolism Reviews 2015, 47 (4) , 534-557. https://doi.org/10.3109/03602532.2015.1086781
    40. Mi Seon Park, Jong-Woo Kim, Inji Park, Hyun-Kyung Lee, Chowon Kim, Changrae Jo, Yoo-Kyung Kim, Byung-Hwa Min, Jaewoong Ryoo, Dong-Seok Lee, Jong-Sup Bae, Sang-Hyun Kim, Sang Kyu Ye, Mae-Ja Park, Hyun-Shik Lee. Characterization of ticlopidine-induced developmental and teratogenic defects in Xenopus embryos and human endothelial cells. Chemico-Biological Interactions 2015, 240 , 172-178. https://doi.org/10.1016/j.cbi.2015.08.017
    41. Sohee Kim, Beom Soo Shin, Eunsook Ma. Synthesis and Caco-2 cell permeability of N-substituted anthranilamide esters as ADP inhibitor in platelets. Archives of Pharmacal Research 2015, 38 (6) , 1147-1156. https://doi.org/10.1007/s12272-014-0353-1
    42. Jaana E. Laine, Merja R. Häkkinen, Seppo Auriola, Risto O. Juvonen, Markku Pasanen. Comparison of trapping profiles between d -peptides and glutathione in the identification of reactive metabolites. Toxicology Reports 2015, 2 , 1024-1032. https://doi.org/10.1016/j.toxrep.2015.07.002
    43. A Tornio, A M Filppula, O Kailari, M Neuvonen, T H Nyrönen, T Tapaninen, P J Neuvonen, M Niemi, J T Backman. Glucuronidation Converts Clopidogrel to a Strong Time-Dependent Inhibitor of CYP2C8: A Phase II Metabolite as a Perpetrator of Drug–Drug Interactions. Clinical Pharmacology & Therapeutics 2014, 96 (4) , 498-507. https://doi.org/10.1038/clpt.2014.141
    44. Amrita Saxena, Girish K. Jain, Hefazat H. Siddiqui, Shom S. Bhunia, Anil K. Saxena, Jiaur R. Gayen. In vitro metabolism of a novel antithrombotic compound, S002-333, and its enantiomers: quantitative cytochrome P450 phenotyping, metabolic profiling and enzyme kinetic studies. Xenobiotica 2014, 44 (4) , 295-308. https://doi.org/10.3109/00498254.2013.831958
    45. Zhexue Wu, Doohyun Lee, Jeongmin Joo, Jung-Hoon Shin, Wonku Kang, Sangtaek Oh, Do Yup Lee, Su-Jun Lee, Sung Su Yea, Hye Suk Lee, Taeho Lee, Kwang-Hyeon Liu. CYP2J2 and CYP2C19 Are the Major Enzymes Responsible for Metabolism of Albendazole and Fenbendazole in Human Liver Microsomes and Recombinant P450 Assay Systems. Antimicrobial Agents and Chemotherapy 2013, 57 (11) , 5448-5456. https://doi.org/10.1128/AAC.00843-13
    46. Laia Tolosa, M. José Gómez-Lechón, Gabriela Pérez-Cataldo, José V. Castell, M. Teresa Donato. HepG2 cells simultaneously expressing five P450 enzymes for the screening of hepatotoxicity: identification of bioactivable drugs and the potential mechanism of toxicity involved. Archives of Toxicology 2013, 87 (6) , 1115-1127. https://doi.org/10.1007/s00204-013-1012-x
    47. Nora M. Hagelberg, Tuukka Saarikoski, Teijo I. Saari, Mikko Neuvonen, Pertti J. Neuvonen, Miia Turpeinen, Mika Scheinin, Kari Laine, Klaus T. Olkkola. Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction. European Journal of Clinical Pharmacology 2013, 69 (4) , 867-875. https://doi.org/10.1007/s00228-012-1433-0
    48. B. Michael Silber, Satish Rao, Kimberly L. Fife, Alejandra Gallardo-Godoy, Adam R. Renslo, Deepak K. Dalvie, Kurt Giles, Yevgeniy Freyman, Manuel Elepano, Joel R. Gever, Zhe Li, Matthew P. Jacobson, Yong Huang, Leslie Z. Benet, Stanley B. Prusiner. Pharmacokinetics and Metabolism of 2-Aminothiazoles with Antiprion Activity in Mice. Pharmaceutical Research 2013, 30 (4) , 932-950. https://doi.org/10.1007/s11095-012-0912-4
    49. Jawed Fareed, Walter Jeske, Indermohan Thethi. Metabolic differences of current thienopyridine antiplatelet agents. Expert Opinion on Drug Metabolism & Toxicology 2013, 9 (3) , 307-317. https://doi.org/10.1517/17425255.2013.749238
    50. Evan D. Kharasch, Kristi Stubbert. Role of Cytochrome P4502B6 in Methadone Metabolism and Clearance. The Journal of Clinical Pharmacology 2013, 53 (3) , 305-313. https://doi.org/10.1002/jcph.1
    51. Fuying Du, Qian Ruan, Mingshe Zhu, Jie Xing. Detection and characterization of ticlopidine conjugates in rat bile using high‐resolution mass spectrometry: applications of various data acquisition and processing tools. Journal of Mass Spectrometry 2013, 48 (3) , 413-422. https://doi.org/10.1002/jms.3170
    52. Joseph A. Jakubowski, Atsuhiro Sugidachi. Thienopyridyl and Direct‐Acting P2Y 12 Receptor Antagonist Antiplatelet Drugs. 2012, 141-164. https://doi.org/10.1002/9783527651085.ch6
    53. . Bioactivation and Inactivation of Cytochrome P450 and Other Drug‐Metabolizing Enzymes. 2012, 43-70. https://doi.org/10.1002/9783527655748.ch3
    54. Hong Liu, Richard Voorman. ADME of Cardiovascular Drugs. 2012, 1-40. https://doi.org/10.1002/9780470921920.edm041
    55. Bo Wiinberg, Lisbeth R. Jessen, Inge Tarnow, Annemarie T. Kristensen. Diagnosis and treatment of platelet hyperactivity in relation to thrombosis in dogs and cats. Journal of Veterinary Emergency and Critical Care 2012, 22 (1) , 42-58. https://doi.org/10.1111/j.1476-4431.2011.00708.x
    56. Deepak K. Dalvie. Bioactivation I: Bioactivation by Cytochrome P450s. 2012, 1-54. https://doi.org/10.1002/9780470921920.edm072
    57. Peng Huang, Rui Zhang, Yongjiu Liang, Dewen Dong. Lawesson's reagent-initiated domino reaction of aminopropenoyl cyclopropanes: synthesis of thieno[3,2-c]pyridinones. Organic & Biomolecular Chemistry 2012, 10 (8) , 1639. https://doi.org/10.1039/c2ob06709a
    58. Chikaaki Motoda, Hironori Ueda, Yasuhiko Hayashi, Mamoru Toyofuku, Tomokazu Okimoto, Masaya Otsuka, Hiromichi Tamekiyo, Tomoharu Kawase, Yasuki Kihara. Impact of Platelet Reactivity to Adenosine Diphosphate Before Implantation of Drug-Eluting Stents on Subsequent Adverse Cardiac Events in Patients With Stable Angina. Circulation Journal 2012, 76 (3) , 641-649. https://doi.org/10.1253/circj.CJ-11-0435
    59. Jeffrey P. Walterscheid, Terry J. Danielson. Tricyclic Antidepressant Drug Interactions. 2012, 193-214. https://doi.org/10.1007/978-1-61779-222-9_5
    60. Kaisa A. Salminen, Achim Meyer, Peter Imming, Hannu Raunio. CYP2C19 Progress Curve Analysis and Mechanism-Based Inactivation by Three Methylenedioxyphenyl Compounds. Drug Metabolism and Disposition 2011, 39 (12) , 2283-2289. https://doi.org/10.1124/dmd.111.041319
    61. Haoming Zhang, Hemali Amunugama, Sarah Ney, Nyemade Cooper, Paul F. Hollenberg. Mechanism-Based Inactivation of Human Cytochrome P450 2B6 by Clopidogrel: Involvement of Both Covalent Modification of Cysteinyl Residue 475 and Loss of Heme. Molecular Pharmacology 2011, 80 (5) , 839-847. https://doi.org/10.1124/mol.111.073783
    62. Chun Yip Chan, Lee Sun New, Han Kiat Ho, Eric Chun Yong Chan. Reversible time-dependent inhibition of cytochrome P450 enzymes by duloxetine and inertness of its thiophene ring towards bioactivation. Toxicology Letters 2011, 206 (3) , 314-324. https://doi.org/10.1016/j.toxlet.2011.07.019
    63. M A Peltoniemi, T I Saari, N M Hagelberg, P Reponen, M Turpeinen, K Laine, P J Neuvonen, K T Olkkola. Exposure to Oral S-ketamine Is Unaffected by Itraconazole but Greatly Increased by Ticlopidine. Clinical Pharmacology & Therapeutics 2011, 90 (2) , 296-302. https://doi.org/10.1038/clpt.2011.140
    64. James R. Halpert. Structure and Function of Cytochromes P450 2B: From Mechanism-Based Inactivators to X-Ray Crystal Structures and Back. Drug Metabolism and Disposition 2011, 39 (7) , 1113-1121. https://doi.org/10.1124/dmd.111.039719
    65. Shinji Shimizu, Ryo Atsumi, Tsunenori Nakazawa, Takashi Izumi, Kenichi Sudo, Osamu Okazaki, Hideo Saji. Ticlopidine-induced hepatotoxicity in a GSH-depleted rat model. Archives of Toxicology 2011, 85 (4) , 347-353. https://doi.org/10.1007/s00204-010-0594-9
    66. Diansong Zhou, Tommy B. Andersson, Scott W. Grimm. In Vitro Evaluation of Potential Drug-Drug Interactions with Ticagrelor: Cytochrome P450 Reaction Phenotyping, Inhibition, Induction, and Differential Kinetics. Drug Metabolism and Disposition 2011, 39 (4) , 703-710. https://doi.org/10.1124/dmd.110.037143
    67. Daniel Mansuy, Patrick M. Dansette. Sulfenic acids as reactive intermediates in xenobiotic metabolism. Archives of Biochemistry and Biophysics 2011, 507 (1) , 174-185. https://doi.org/10.1016/j.abb.2010.09.015
    68. Jyothi C. Talakad, Manish B. Shah, Gregory S. Walker, Cathie Xiang, James R. Halpert, Deepak Dalvie. Comparison of In Vitro Metabolism of Ticlopidine by Human Cytochrome P450 2B6 and Rabbit Cytochrome P450 2B4. Drug Metabolism and Disposition 2011, 39 (3) , 539-550. https://doi.org/10.1124/dmd.110.037101
    69. Anastazia A. Kei, Matilda Florentin, Dimitri P. Mikhailidis, Moses S. Elisaf, Evangelos N. Liberopoulos. Review: Antiplatelet Drugs: What Comes Next?. Clinical and Applied Thrombosis/Hemostasis 2011, 17 (1) , 9-26. https://doi.org/10.1177/1076029610385222
    70. D. Mansuy. Brief historical overview and recent progress on cytochromes P450: Adaptation of aerobic organisms to their chemical environment and new mechanisms of prodrug bioactivation. Annales Pharmaceutiques Françaises 2011, 69 (1) , 62-69. https://doi.org/10.1016/j.pharma.2010.11.001
    71. Yuichi Kinoshita, Naoki Matsumoto, Minoru Watanabe, Yuko Takeba, Yutoku Yoshida, Keiichiro Ohba, Satoshi Suzuki, Fumio Itoh, Toshio Kumai, Shinichi Kobayashi. Comparison of the Effects of Omeprazole and Rabeprazole on Ticlopidine Metabolism In Vitro. Journal of Pharmacological Sciences 2011, 117 (1) , 19-26. https://doi.org/10.1254/jphs.11048FP
    72. Marie‐Claude Duhamel, Éric Troncy, Francis Beaudry. Metabolic stability and determination of cytochrome P450 isoenzymes' contribution to the metabolism of medetomidine in dog liver microsomes. Biomedical Chromatography 2010, 24 (8) , 868-877. https://doi.org/10.1002/bmc.1379
    73. Dan Rock, Larry C. Wienkers. Characterization of Cytochrome P 450 Mechanism‐Based Inhibition. 2010, 1-56. https://doi.org/10.1002/9780470571224.pse117
    74. Leonid G Voskressensky, Modesto de Candia, Andrea Carotti, Tatiana N Borisova, Larisa N Kulikova, Alexey V Varlamov, Cosimo Altomare. Investigation on the antiplatelet activity of pyrrolo[3,2- c ]pyridine-containing compounds. Journal of Pharmacy and Pharmacology 2010, 55 (3) , 323-332. https://doi.org/10.1211/002235702676
    75. Nagy A. Farid, Atsushi Kurihara, Steven A. Wrighton. Metabolism and Disposition of the Thienopyridine Antiplatelet Drugs Ticlopidine, Clopidogrel, and Prasugrel in Humans. The Journal of Clinical Pharmacology 2010, 50 (2) , 126-142. https://doi.org/10.1177/0091270009343005
    76. Noritaka Ariyoshi, Yukako Iga, Koji Hirata, Yasunori Sato, Go Miura, Itsuko Ishii, Seiji Nagamori, Mitsukazu Kitada. Enhanced Susceptibility of HLA-mediated Ticlopidine-induced Idiosyncratic Hepatotoxicity by CYP2B6 Polymorphism in Japanese. Drug Metabolism and Pharmacokinetics 2010, 25 (3) , 298-306. https://doi.org/10.2133/dmpk.25.298
    77. Y. Nishiya, K. Nakamura, N. Okudaira, K. Abe, N. Kobayashi, O. Okazaki. Effects of organic solvents on the time-dependent inhibition of CYP3A4 by diazepam. Xenobiotica 2010, 40 (1) , 1-8. https://doi.org/10.3109/00498250903337392
    78. Marta Kot, Władysława A. Daniel. Effect of diethyldithiocarbamate (DDC) and ticlopidine on CYP1A2 activity and caffeine metabolism: an in vitro comparative study with human cDNA-expressed CYP1A2 and liver microsomes. Pharmacological Reports 2009, 61 (6) , 1216-1220. https://doi.org/10.1016/S1734-1140(09)70187-2
    79. Y. Nishiya, K. Hagihara, A. Kurihara, N. Okudaira, N.A. Farid, O. Okazaki, T. Ikeda. Comparison of mechanism-based inhibition of human cytochrome P450 2C19 by ticlopidine, clopidogrel, and prasugrel. Xenobiotica 2009, 39 (11) , 836-843. https://doi.org/10.3109/00498250903191427
    80. Mauricio Cabrera, María Laura Lavaggi, Paola Hernández, Alicia Merlino, Alejandra Gerpe, Williams Porcal, Mariana Boiani, Ana Ferreira, Antonio Monge, Adela López de Cerain, Mercedes González, Hugo Cerecetto. Cytotoxic, mutagenic and genotoxic effects of new anti-T. cruzi 5-phenylethenylbenzofuroxans. Contribution of phase I metabolites on the mutagenicity induction. Toxicology Letters 2009, 190 (2) , 140-149. https://doi.org/10.1016/j.toxlet.2009.07.006
    81. Shinji Shimizu, Ryo Atsumi, Tsunenori Nakazawa, Yuko Fujimaki, Kenichi Sudo, Osamu Okazaki. Metabolism of Ticlopidine in Rats: Identification of the Main Biliary Metabolite as a Glutathione Conjugate of Ticlopidine S -Oxide. Drug Metabolism and Disposition 2009, 37 (9) , 1904-1915. https://doi.org/10.1124/dmd.109.027524
    82. Scott W. Grimm, Heidi J. Einolf, Steven D. Hall, Kan He, Heng-Keang Lim, Kah-Hiing John Ling, Chuang Lu, Amin A. Nomeir, Eleanore Seibert, Konstantine W. Skordos, George R. Tonn, Robert Van Horn, Regina W. Wang, Y. Nancy Wong, Tian J. Yang, R. Scott Obach. The Conduct of in Vitro Studies to Address Time-Dependent Inhibition of Drug-Metabolizing Enzymes: A Perspective of the Pharmaceutical Research and Manufacturers of America. Drug Metabolism and Disposition 2009, 37 (7) , 1355-1370. https://doi.org/10.1124/dmd.109.026716
    83. Srikanth Nagalla, Suzanne M. Leal, Paul F. Bray. Pharmacogenomics of Platelet Inhibitors. 2009, 49-66. https://doi.org/10.3109/9781420069242.005
    84. Shu-Feng Zhou, Jun-Ping Liu, Balram Chowbay. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metabolism Reviews 2009, 41 (2) , 89-295. https://doi.org/10.1080/03602530902843483
    85. David M. Stresser, Andrew K. Mason, Elke S. Perloff, Thuy Ho, Charles L. Crespi, Andre A. Dandeneau, Ling Morgan, Shangara S. Dehal. Differential Time- and NADPH-Dependent Inhibition of CYP2C19 by Enantiomers of Fluoxetine. Drug Metabolism and Disposition 2009, 37 (4) , 695-698. https://doi.org/10.1124/dmd.108.025726
    86. Yumi Nishiya, Katsunobu Hagihara, Takashi Ito, Masami Tajima, Shin-ichi Miura, Atsushi Kurihara, Nagy A. Farid, Toshihiko Ikeda. Mechanism-Based Inhibition of Human Cytochrome P450 2B6 by Ticlopidine, Clopidogrel, and the Thiolactone Metabolite of Prasugrel. Drug Metabolism and Disposition 2009, 37 (3) , 589-593. https://doi.org/10.1124/dmd.108.022988
    87. Dan Rock, Larry C. Wienkers. Characterization of Cytochrome P450 Mechanism‐Based Inhibition. 2009, 479-534. https://doi.org/10.1002/9780470439265.ch18
    88. Yael Garten, Russ B Altman. Pharmspresso: a text mining tool for extraction of pharmacogenomic concepts and relationships from full text. BMC Bioinformatics 2009, 10 (S2) https://doi.org/10.1186/1471-2105-10-S2-S6
    89. Hideo Takakusa, Hiroshi Masumoto, Chie Makino, Osamu Okazaki, Kenichi Sudo. Quantitative Assessment of Reactive Metabolite Formation using 35S-labeled Glutathione. Drug Metabolism and Pharmacokinetics 2009, 24 (1) , 100-107. https://doi.org/10.2133/dmpk.24.100
    90. Hiroshi Yasuda, Masaya Yamada, Susumu Sawada, Yutaka Endo, Kazuaki Inoue, Fuyuki Asano, Youichi Takeyama, Makoto Yoshiba. Upper Gastrointestinal Bleeding in Patients Receiving Dual Antiplatelet Therapy after Coronary Stenting. Internal Medicine 2009, 48 (19) , 1725-1730. https://doi.org/10.2169/internalmedicine.48.2031
    91. Marie Louise Brezniceanu, Alain Deroussent, Helen Gu, James B. Mangold, Hilmar Schiller, Gerhard Gross, Thierry Cresteil. Oxidative Metabolism of Epothilones A and B (Patupilone) by Cytochromes P450: Involvement of CYP3A and CYP2C. The Open Drug Metabolism Journal 2008, 2 (1) , 14-23. https://doi.org/10.2174/1874073100802010014
    92. Olavi Pelkonen, Miia Turpeinen, Jukka Hakkola, Paavo Honkakoski, Janne Hukkanen, Hannu Raunio. Inhibition and induction of human cytochrome P450 enzymes: current status. Archives of Toxicology 2008, 82 (10) , 667-715. https://doi.org/10.1007/s00204-008-0332-8
    93. Hideo Takakusa, Hiroshi Masumoto, Ayako Mitsuru, Osamu Okazaki, Kenichi Sudo. Markers of Electrophilic Stress Caused by Chemically Reactive Metabolites in Human Hepatocytes. Drug Metabolism and Disposition 2008, 36 (5) , 816-823. https://doi.org/10.1124/dmd.107.018002
    94. Qi-Biao Su, Fan He, Xue-Ding Wang, Su Guan, Zhi-Yong Xie, Lai-You Wang, Yu-Jing Lu, Lian-Quan Gu, Zhi-Shu Huang, Xiao Chen, Min Huang, Shu-Feng Zhou. Biotransformation and pharmacokinetics of the novel anticancer drug, SYUIQ-5, in the rat. Investigational New Drugs 2008, 26 (2) , 119-137. https://doi.org/10.1007/s10637-007-9089-9
    95. Rebecca Stadel, Jun Yang, Julia W. Nalwalk, James G. Phillips, Lindsay B. Hough. High-Affinity Binding of [ 3 H]Cimetidine to a Heme-Containing Protein in Rat Brain. Drug Metabolism and Disposition 2008, 36 (3) , 614-621. https://doi.org/10.1124/dmd.107.017889
    96. Damaris S. Diaz, Michael. P. Kozar, Kirsten S. Smith, Constance O. Asher, Jason C. Sousa, Guy A. Schiehser, David. P. Jacobus, Wilbur. K. Milhous, Donald. R. Skillman, Todd. W. Shearer. Role of Specific Cytochrome P450 Isoforms in the Conversion of Phenoxypropoxybiguanide Analogs in Human Liver Microsomes to Potent Antimalarial Dihydrotriazines. Drug Metabolism and Disposition 2008, 36 (2) , 380-385. https://doi.org/10.1124/dmd.106.013920
    97. K Hirata, H Takagi, M Yamamoto, T Matsumoto, T Nishiya, K Mori, S Shimizu, H Masumoto, Y Okutani. Ticlopidine-induced hepatotoxicity is associated with specific human leukocyte antigen genomic subtypes in Japanese patients: a preliminary case–control study. The Pharmacogenomics Journal 2008, 8 (1) , 29-33. https://doi.org/10.1038/sj.tpj.6500442
    98. William W. Johnson. Cytochrome P450 Inactivation by Pharmaceuticals and Phytochemicals: Therapeutic Relevance. Drug Metabolism Reviews 2008, 40 (1) , 101-147. https://doi.org/10.1080/03602530701836704
    99. Katsunobu Hagihara, Yumi Nishiya, Atsushi Kurihara, Miho Kazui, Nagy A. Farid, Toshihiko Ikeda. Comparison of Human Cytochrome P450 Inhibition by the Thienopyridines Prasugrel, Clopidogrel, and Ticlopidine. Drug Metabolism and Pharmacokinetics 2008, 23 (6) , 412-420. https://doi.org/10.2133/dmpk.23.412
    100. Paul F. Hollenberg, Ute M. Kent, Namandjé N. Bumpus. Mechanism-Based Inactivation of Human Cytochromes P450s: Experimental Characterization, Reactive Intermediates, and Clinical Implications. Chemical Research in Toxicology 2008, 21 (1) , 189-205. https://doi.org/10.1021/tx7002504
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