Novel binding mode of the acidic CYP2D6 substrates pactimibe and its metabolite R-125528

Drug Metabolism and Disposition

Volumn 36, Issue 9, 2008, Pages 1938-1943

  Kotsuma, Masakatsu ^a   Hanzawa, Hiroyuki ^a   Iwata, Yoriko ^a   Takahashi, Kenji ^b   Tokui, Taro ^a  

^a DAIICHI SANKYO CO   (Japan)

^b Research Laboratories   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

AMITRIPTYLINE; BUFURALOL; CYTOCHROME P450 2D6; DEBRISOQUINE; DESIPRAMINE; DEXTROMETHORPHAN; DRUG METABOLITE; IMIPRAMINE; KV 2908; KV 2909; KV 2915; METOPROLOL; NORTRIPTYLINE; PACTIMIBE; PROPAFENONE; PROPRANOLOL; R 125528; SPIROSULFONAMIDE; SULFONAMIDE; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CRYSTAL STRUCTURE; ENZYME BINDING; ENZYME METABOLISM; ENZYME SUBSTRATE; HYDROPHOBICITY; MICHAELIS CONSTANT; MOLECULAR DOCKING; MOLECULAR INTERACTION; MOLECULAR WEIGHT; NONHUMAN; PKA; PRIORITY JOURNAL;

ACETYL-COA C-ACYLTRANSFERASE; ALKANES; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; CYTOCHROME P-450 CYP2D6; HUMANS; INDOLEACETIC ACIDS; INDOLES; MASS SPECTROMETRY; SUBSTRATE SPECIFICITY;

EID: 50049122372     PISSN: 00909556     EISSN: 1521009X     Source Type: Journal    
DOI: 10.1124/dmd.108.020776     Document Type: Article

References (38)

1. Brynne N, Dalén P, Alván G, Bertilsson L, and Gabrielsson J (1998) Influence of CYP2D6 polymorphism on the pharmacokinetics and pharmacodynamic of tolterodine. Clin Pharmacol Ther 63:529-539.
2. de Graaf C, Oostenbrink C, Keizers PH, van Vugt-Lussenburg BM, van Waterschoot RA, Tschirret-Guth RA, Commandeur JN, and Vermeulen NP (2007) Molecular modeling-guided site-directed mutagenesis of cytochrome P450 2D6. Curr Drug Metab 8:59-77.
3. de Groot MJ, Ackland MJ, Horne VA, Alex AA, and Jones BC (1999a) Novel approach to predicting P450-mediated drug metabolism: development of a combined protein and pharmacophore model for CYP2D6. J Med Chem 42:1515-1524.
4. de Groot MJ, Ackland MJ, Horne VA, Alex AA, and Jones BC (1999b) A novel approach to predicting P450 mediated drug metabolism. CYP2D6 catalyzed N-dealkylation reactions and qualitative metabolite predictions using a combined protein and pharmacophore model for CYP2D6. J Med Chem 42:4062-4070.
5. Ekins S, Berbaum J, and Harrison RK (2003) Generation and validation of rapid computational filters for CYP2d6 and CYP3a4. Drug Metab Dispos 31:1077-1080.
6. Ellis SW, Hayhurst GP, Smith G, Lightfoot T, Wong MM, Simula AP, Ackland MJ, Sternberg MJ, Lennard MS, Tucker GT, et al. (1995) Evidence that aspartic acid 301 is a critical substrate-contact residue in the active site of cytochrome P450 2D6. J Biol Chem 270:29055-29058.
7. Emoto C, Murase S, and Iwasaki K (2006) Approach to the prediction of the contribution of major cytochrome P450 enzymes to drug metabolism in the early drug-discovery stage. Xenobiotica 36:671-683.
8. 120 contributes to the regiospecificity of cytochrome P450 2D6: mutation leads to the formation of a novel dextromethorphan metabolite. Biochem J 380:353-360.
9. Fux R, Mörike K, Pröhmer AM, Delabar U, Schwab M, Schaeffeler E, Lorenz G, Gleiter CH, Eichelbaum M, and Kivistö KT (2005) Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther 78:378-387.
10. Guengerich FP (2001) Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 14:611-650.
11. Guengerich FP, Hanna IH, Martin MV, and Gillam EM (2003) Role of glutamic acid 216 in cytochrome P450 2D6 substrate binding and catalysis. Biochemistry 42:1245-1253.
12. Guengerich FP, Miller GP, Hanna IH, Martin MV, Léger S, Black C, Chauret N, Silva JM, Trimble LA, Yergey JA, et al. (2002) Diversity in the oxidation of substrates by cytochrome P450 2D6: lack of an obligatory role of aspartate 301-substrate electrostatic bonding. Biochemistry 41:11025-11034.
13. Jones BC, Tyman CA, and Smith DA (1997) Identification of the cytochrome P450 isoforms involved in the O-demethylation of 4-nitroanisole in human liver microsomes. Xenobiotica 27:1025-1037.
14. Kamiya S, Shirahase H, Matsui H, Nakamura S, and Wada K (1997) inventors; PCT International. Novel heterocyclic derivatives and medicinal use thereof. World patent WO9712860, 1997 Apr 10.
15. Kamiya S, Shirahase H, Matsui H, Nakamura S, and Wada K (2000) inventors; Indolyl and indolinyl derivatives and medical use thereof as ACAT or lipid peroxidation inhibitors. U.S. patent 6063806. 2000 May 16.
16. Keizers PH, Lussenburg BM, de Graaf C, Mentink LM, Vermeulen NP, and Commandeur JN (2004) Influence of phenylalanine 120 on cytochrome P450 2D6 catalytic selectivity and regiospecificity: crucial role in 7-methoxy-4- (aminomethyl)-coumarin metabolism. Biochem Pharmacol 68:2263-2271.
17. Kemp CA, Flanagan JU, van Eldik AJ, Maréchal JD, Wolf CR, Roberts GC, Paine MJ, and Sutcliffe MJ (2004) Validation of model of cytochrome P450 2D6: an in silico tool for predicting metabolism and inhibition. J Med Chem 47:5340-5346.
18. Kitayama K, Koga T, Inaba T, and Fujioka T (2006a) Multiple mechanisms of hypocholesterolemic action of pactimibe, a novel acyl-coenzyme A:cholesterol acyltransferase inhibitor. Eur J Pharmacol 543:123-132.
19. Kitayama K, Koga T, Maeda N, Inaba T, and Fujioka T (2006b) Pactimibe stabilizes atherosclerotic plaque through macrophage acyl-CoA:cholesterol acyltransferase inhibition in WHHL rabbits. Eur J Pharmacol 539:81-88.
20. Kitayama K, Tanimoto T, Koga T, Terasaka N, Fujioka T, and Inaba T (2006c) Importance of acyl-coenzyme A:cholesterol acyltransferase 1/2 dual inhibition for anti-atherosclerotic potency of pactimibe. Eur J Pharmacol 540:121-130.
21. Kotsuma M, Tokui T, Freudenthaler S, and Nishimura K (2008a) Effects of ketoconazole and quinidine on pharmacokinetics of pactimibe and its plasma metabolite, R-125528, in human. Drug Metab Dispos, in press.
22. Kotsuma M, Tokui T, Ishizuka-Ozeki T, Honda T, Iwabuchi H, Murai T, Ikeda T, and Saji H (2008b) CYP2D6-Mediated metabolism of a novel acyl coenzyme A:cholesterol acyltransferase inhibitor, pactimibe, and its unique plasma metabolite, R-125528. Drug Metab Dispos 36:529-534.
23. Koymans L, Vermeulen NP, van Acker SA, te Koppele JM, Heykants JJ, Lavrijsen K, Meuldermans W, and Donné-Op den Kelder GM (1992) A predictive model for substrates of cytochrome P450-debrisoquine (2D6). Chem Res Toxicol 5:211-219.
24. Kumar GN, Rodrigues AD, Buko AM, and Denissen JF (1996) Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 277:423-431.
25. Lewis DF (2004) Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes. Toxicol In Vitro 18:89-97.
26. Molden E, Johansen PW, Bøe GH, Bergan S, Christensen H, Rugstad HE, Rootwelt H, Reubsaet L, and Lehne G (2002) Pharmacokinetics of diltiazem and its metabolites in relation to CYP2D6 genotype. Clin Pharmacol Ther 72:333-342.
27. Nissen SE, Tuzcu EM, Brewer HB, Sipahi I, Nicholls SJ, Ganz P, Schoenhagen P, Waters DD, Pepine CJ, Crowe TD, et al. (2006) Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 354:1253-1263.
28. Niwa T, Yabusaki Y, Honma K, Matsuo N, Tatsuta K, Ishibashi F, and Katagiri M (1998) Contribution of human hepatic cytochrome P450 isoforms to regioselective hydroxylation of steroid hormones. Xenobiotica 28:539-547.
29. Obach RS and Reed-Hagen AE (2002) Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab Dispos 30:831-837.
30. Paine MJ, McLaughlin LA, Flanagan JU, Kemp CA, Sutcliffe MJ, Roberts GC, and Wolf CR (2003) Residues glutamate 216 and aspartate 301 are key determinants of substrate specificity and product regioselectivity in cytochrome P450 2D6. J Biol Chem 278:4021-4027.
31. Rowland P, Blaney FE, Smyth MG, Jones JJ, Leydon VR, Oxbrow AK, Lewis CJ, Tennant MG, Modi S, Eggleston DS, Chenery RJ, and Bridges AM (2006) Crystal structure of human cytochrome P450 2D6. J Biol Chem 281:7614-7622.
32. Shen H, He MM, Liu H, Wrighton SA, Wang L, Guo B, and Li C (2007) Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos 35:1292-1300.
33. Sherman W, Day T, Jacobson MP, Friesner RA, and Farid R (2006) Novel procedure for modeling ligand/receptor induced fit effects. J Med Chem 49:534-553.
34. Smith G, Modi S, Pillai I, Lian LY, Sutcliffe MJ, Pritchard MP, Friedberg T, Roberts GC, and Wolf CR (1998) Determinants of the substrate specificity of human cytochrome P-450 CYP2D6: design and construction of a mutant with testosterone hydroxylase activity. Biochem J 331 (Pt 3):783-792.
35. Strobl GR, von Kruedener S, Stöckigt J, Guengerich FP, and Wolff T (1993) Development of a pharmacophore for inhibition of human liver cytochrome P-450 2D6: molecular modeling and inhibition studies. J Med Chem 36:1136-1145.
36. Uttamsingh V, Lu C, Miwa G, and Gan LS (2005) Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos 33:1723-1728.
37. van der Weide J and Steijns LS (1999) Cytochrome P450 enzyme system: genetic polymorphisms and impact on clinical pharmacology. Ann Clin Biochem 36 (Pt 6):722-729.
38. Venkatakrishnan K, von Moltke LL, and Greenblatt DJ (1999) Nortriptyline E-10-hydroxylation in vitro is mediated by human CYP2D6 (high affinity) and CYP3A4 (low affinity): implications for interactions with enzyme-inducing drugs. J Clin Pharmacol 39:567-577.