| Title : Multiple Cytochrome P450 Isoforms Are Involved in the Generation of a Pharmacologically Active Thiol Metabolite, whereas Paraoxonase 1 and Carboxylesterase 1 Catalyze the Formation of a Thiol Metabolite Isomer from Ticlopidine - Kim_2014_Drug.Metab.Dispos_42_141 |
| Author(s) : Kim MJ , Jeong ES , Park JS , Lee SJ , Ghim JL , Choi CS , Shin JG , Kim DH |
| Ref : Drug Metabolism & Disposition: The Biological Fate of Chemicals , 42 :141 , 2014 |
| Abstract : Ticlopidine is a first-generation thienopyridine antiplatelet drug that prevents adenosine 5'-diphosphate (ADP)-induced platelet aggregation. We identified the enzymes responsible for the two-step metabolic bioactivation of ticlopidine in human liver microsomes and plasma. Formation of 2-oxo-ticlopidine, an intermediate metabolite, was NADPH dependent and cytochrome P450 (CYP) 1A2, 2B6, 2C19, and 2D6 were involved in this reaction. Conversion of 2-oxo-ticlopidine to thiol metabolites was observed in both microsomes (M1 and M2) and plasma (M1). These two metabolites were considered as isomers, and mass spectral analysis suggested that M2 was a thiol metabolite bearing an exocyclic double bond, whereas M1 was an isomer in which the double bond was migrated to an endocyclic position in the piperidine ring. The conversion of 2-oxo-ticlopidine to M1 in plasma was significantly increased by the addition of 1 mM CaCl2. In contrast, the activity in microsomes was not changed in the presence of CaCl2. M1 formation in plasma was inhibited by EDTA but not by other esterase inhibitors, whereas this activity in microsomes was substantially inhibited by carboxylesterase (CES) inhibitors such as bis-(p-nitrophenyl)phosphate (BNPP), diisopropylphosphorofluoride (DFP), and clopidogrel. The conversion of 2-oxo-ticlopidine to M1 was further confirmed with recombinant paraoxonase 1 (PON1) and CES1. However, M2 was detected only in NADPH-dependent microsomal incubation, and multiple CYP isoforms were involved in M2 formation with highest contribution of CYP2B6. In vitro platelet aggregation assay demonstrated that M2 was pharmacologically active. These results collectively indicated that the formation of M2 was mediated by CYP isoforms whereas M1, an isomer of M2, was generated either by human PON1 in plasma or by CES1 in the human liver. |
| ESTHER : Kim_2014_Drug.Metab.Dispos_42_141 |
| PubMedSearch : Kim_2014_Drug.Metab.Dispos_42_141 |
| PubMedID: 24170778 |
| Gene_locus related to this paper: human-CES1 |
| Gene_locus related to this paper: human-CES1 |
Kim MJ, Jeong ES, Park JS, Lee SJ, Ghim JL, Choi CS, Shin JG, Kim DH (2014)
Multiple Cytochrome P450 Isoforms Are Involved in the Generation of a Pharmacologically Active Thiol Metabolite, whereas Paraoxonase 1 and Carboxylesterase 1 Catalyze the Formation of a Thiol Metabolite Isomer from Ticlopidine
Drug Metabolism & Disposition: The Biological Fate of Chemicals
42 :141
Kim MJ, Jeong ES, Park JS, Lee SJ, Ghim JL, Choi CS, Shin JG, Kim DH (2014)
Drug Metabolism & Disposition: The Biological Fate of Chemicals
42 :141