DMD #048264 1 Discovery and Characterization of Novel, Potent ...

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DMD #048264 Running title: Discovery of novel, potent, and selective CYP2J2 inhibitors Corresponding author address: Li Chen, Ph.D. School of Life Science and Technology, Tongji University 1239 Si Ping Road Shanghai 200092 lichen@huamedicine.com Number of text pages: 41 Number of tables: 4 Number of figures: 8 Number of References: 59 Words in Abstract: 249 Words in Introduction: 749 Words in Discussion: 1500 List of abbreviations: astemizole (AST), cytochrome P450 (CYP), cytochrome P450 2J2 (CYP2J2), drug-drug interaction (DDI), O-desmethyl astemizole (DES-AST), human liver microsome (HLM), liquid chromatography-tandem mass spectrometry (LC-MS/MS), nicotinamide adenine dinucleotide phosphate (NADPH), time-dependent inhibition (TDI) 2
DMD #048264 Abstract Cytochrome P450 (CYP) 2J2 is one of the human CYPs involved in phase I xenobiotics metabolism. It is mainly expressed in extrahepatic tissues including intestine and cardiovascular systems. The general role of CYP2J2 in drug metabolism is not yet fully understood, while the recent discovery that CYP2J2 can metabolize a wide range of structurally diverse drugs and its primary distribution in the intestine suggest its potentially indispensable role in first-pass intestinal metabolism and involvement in drug- drug interaction (DDI). To fully characterize its role in drug metabolism selective and potent inhibitors of CYP2J2 are necessary tools. In the current study, 69 known drugs have been screened for the inhibition of CYP2J2 and we have discovered a number of marketed drugs as potent and selective CYP2J2 inhibitors. In particular, telmisartan and flunarizine have CYP2J2 inhibition IC50 values of 0.42 and 0.94 μM, respectively, which are at least 10-fold more selective against all other major metabolizing CYPs; moreover, they are not substrate of CYP2J2 and show no time-dependent inhibition (TDI) toward this CYP. The results of enzyme kinetics studies, supported by molecular modeling, have also elucidated that telmisartan is a mixed type inhibitor while flunarizine competitively inhibits CYP2J2. The Ki for telmisartan is 0.19 μM with an α value, an indicator of the type of inhibition mechanism, of 2.80, while flunarizine has a Ki value of 0.13 μM. These newly discovered CYP2J2 inhibitors can be potentially used as a tool to study CYP2J2 in drug metabolism and interaction in a clinical setting. 3
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Page 5 and 6: DMD #048264 its rather broad substr
Page 7 and 8: DMD #048264 role of CYP2J2 in drug
Page 9 and 10: DMD #048264 CYP2C9, CYP2C19, and CY
Page 11 and 12: DMD #048264 AST, DES-AST, and IS, r
Page 13 and 14: DMD #048264 where v is the reaction
Page 15 and 16: DMD #048264 = ΔEelec + ΔEvdW + Δ
Page 17 and 18: DMD #048264 Paine et al., 2006) and
Page 19 and 20: DMD #048264 plot does not go throug
Page 21 and 22: DMD #048264 surface for telmisartan
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Page 25 and 26: DMD #048264 subsequently confirmed
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Page 29 and 30: DMD #048264 References Baron A, Fri
Page 31 and 32: DMD #048264 Lafite P, Dijols S, Zel
Page 33 and 34: DMD #048264 Young CL, Dias VC, and
Page 35 and 36: DMD #048264 Figure Legends FIGURE 1
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Page 39 and 40: DMD #048264 Table 2: Probe substrat
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