Predicting the oxidative metabolism of statins: An application of the MetaSite® algorithm

Pharmaceutical Research

Volumn 24, Issue 3, 2007, Pages 480-501

  Caron, Giulia ^a   Ermondi, Giuseppe ^a   Testa, Bernard ^b  

^a UNIVERSITY OF TURIN   (Italy)

^b LAUSANNE UNIVERSITY HOSPITAL   (Switzerland)

Author keywords

in silico; Metabolism prediction; MetaSite; Molecular fields; Statins

Indexed keywords

ATORVASTATIN; CERIVASTATIN; CYTOCHROME P450 1A2; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; DRUG METABOLITE; FLUINDOSTATIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LACTONE; MEVINOLIN; PITAVASTATIN; PRAVASTATIN; PRODRUG; SIMVASTATIN;

ALGORITHM; ARTICLE; CHEMICAL REACTION; CRYSTALLOGRAPHY; DRUG METABOLISM; DRUG STRUCTURE; EQUILIBRIUM CONSTANT; EXPERIMENTAL STUDY; FALSE POSITIVE RESULT; OXIDATION; PRIORITY JOURNAL; PROBABILITY; THREE DIMENSIONAL IMAGING;

ALGORITHMS; ANIMALS; CYTOCHROME P-450 ENZYME SYSTEM; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; OXIDATION-REDUCTION; REPRODUCIBILITY OF RESULTS; SOFTWARE DESIGN; SOFTWARE VALIDATION; TECHNOLOGY, PHARMACEUTICAL;

EID: 33847099636     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-006-9199-7     Document Type: Article

References (65)

1. B. Testa and G. Cruciani. Structure-metabolism relations, and the challenge of predicting biotransformation. In B. Testa, H. van de Waterbeemd, G. Folkers, and R. H. Guy (eds.), Pharmacokinetic Optimization in Drug Research: Biological, Physicochemical and Computational Chemistry, Wiley-VHCA, Zurich, 2001, pp. 65-84.
2. B. Testa and W. Soine. Principles of drug metabolism. In D. J. Abraham (ed.), Burger's Medicinal Chemistry and Drug Discovery, Wiley-Interscience, Hoboken, N.J., USA, 2003, pp. 431-498.
3. P. W. Erhardt. Metabolism Databases and High. Throughput Tesing During Drug Design and Development, Blackwell Science, London, UK, 1999.
4. S. A. Kulkarni, J. Zhu, and B. S. Lechinger. in silico techniques for the study and prediction of xenobiotic metabolism: a review. Xenobiotica 35:955-973 (2005).
5. B. Testa, A. L. Balmat, and A. Long. Predicting drug metabolism: concepts and challenges. Pure Appl. Chem. 76:907-914 (2004).
6. B. Testa, A. L. Balmat, A. Long, and P. Judson. Predicting drug metabolism - an evaluation of the expert system METEOR. Chem. Biodivers. 2:872-885 (2005).
7. B. Testa, P. Crivori, M. Reist, and P. A. Carrupt. The influence of lipophilicity on the pharmacokinetic behavior of drugs: concepts and examples. Perspect. Drug Discov. Des. 19:179- 211 (2000).
8. C. Hansch, S. B. Mekapati, A. Kurup, and R. P. Verma. QSAR of Cytochrome P450. Drug Metab. Rev. 36:105-156 (2004).
9. J. E. Penzotti, G. A. Landrum, and S. Putta. Building predictive ADMET models for early decisions in drug discovery. Curr. Opin. Drug Discov. Dev. 7:49-61 (2004).
10. D. Korolev, K. V. Balakin, Y. Nikolsky, E. Kirilov, Y. A. Ivanenkov, N. P. Savchuk,A. A. Ivashchenko, and T. Nikolskaya. Modeling of human cytochrome P450-mediated durg metabolism using unsupervised machine learning approach. J. Med. Chem. 46:3631-3643 (2003).
11. D. L. Harris. In silico predictive metabolism: a structural/electronic filter method. Curr. Opin. Drug Discov. Dev.7:43-48 (2004).
12. J. P. Jones, M. Mysinger, and K. R. Korzekwa. Computational models for cytochrome P450: a predictive electronic model for aromatic oxidation and hydrogen atom abstraction. Drug Metab. Dispos. 30:7-12 (2002).
13. R. N. Hines, Z. Luo, T. Cresteil, X. Ding, R. A. Prough, J. L. Fitzpatrick, S. L. Ripp, K. C. Falkner, N.-L. Ge, A. Levine, and C. J. Elferink. Molecular regulation of genes encoding xenobiotic-metabolizing enzymes: mechanisms involving endogeneous factors. Drug Metab. Dispos. 29:623-633 (2001).
14. M. D. Segall, M. C. Payne, S. W. Ellis, G. T. Tucker, and P. J. Eddershaw. First principles investigation of singly reduced cytochrome P450. Xenobiotica 29:561-571 (1999).
15. P. A. Smith, M. J. Sorich, R. A. McKinnon, and J. O. Miners. Pharmacophore and quantitative structureYactivity relationship modeling: complementary approaches for the rationalization and prediction of UDP-glucuronosyltransferase 1A4 substrate selectivity. J. Med. Chem. 46:1617-1626 (2003).
16. S. Ekins, D. M. Stresser, and J. A. Williams. In vitro and pharmacophore insights into CYP3A enzymes. TIPS 24:161-166 (2003).
17. A. Poso, J. Gynther, and R. Juvonen. A comparative molecular field analysis of cytochrome P450 2A5 and 2A6 inhibitors. J. Comput. - Aided Mol. Des. 15:195-202 (2001).
18. L. Afzelius, I. Zamora, C. M. Misimirembwa, A. Karlén, T. B. Andersson, S. Mecucci, M. Baroni, and G. Cruciani. Conformer- and alignment-independent model for predicting structurally diverse competitive CYP2C9 inhibitors. J. Med. Chem. 47:907-914 (2004).
19. I. Zamora, L. Afzelius, and G. Cruciani. Predicting drug metabolism: a site of metabolism prediction tool applied to the cytochrome P450 2C9. J. Med. Chem. 46:2313-2324 (2003).
20. M. J. Sorich, J. O. Miners, R. A. McKinnon, and P. A. Smith. Multiple pharmacophores for the investigation of human UDP-glucuronosyltransferase isoform substare selectivity. Mol. Pharmacol. 65:301-308 (2004).
21. J. Venhoorst, A. M. ter Laak, J. N. M. Commandeur, Y. Funae, T. Hiroi, and N. P. E. Vermeulen. Homology modeling of rat and human cytochrome P450 2D (CYP2D) isoforms and computational rationalization of experimental ligand-binding specificities. J. Med. Chem. 46:74-86 (2003).
22. D. F. V. Lewis. Homology modelling of human CYP2 family enzymes based on the CYP2C5 crystal structure. Xenobiotica 32:305-323 (2002).
23. D. F. V. Lewis. Molecular modeling of human cytochrome P450-substrate interactions. Drug Metab. Rev. 34:55-67 (2002).
24. A. M. ter Laak and N. P. E. Vermeulen. Molecular modeling approaches to predict metabolism and toxicity. In B. Testa, H. van de Waterbeemd, G. Folkers, and R. H. Guy (eds.), Pharmacokinetic Optimization in Drug Research, Wiley-VCH, Zürich, 2001, pp. 551-588.
25. P. A. Williams, J. Cosme, A. Ward, H. C. Angove, D. Vinkovic, and H. Jhoti. Crystal structure of human cytochrome P450 2C9 with bound warfarin. Nature 424:464-468 (2003).
26. P. A. Williams, J. Cosme, D. Vinkovic, A. Ward, H. C. Angove, P. J. Day, C. Vonrhein, I. J. Tickle, and H. Jhoti. Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 305:683-686 (2004).
27. S. Ekins, E. Andreyev, A. Ryabov, E. Kirillov, E. A. Rakhmatulin, A. Bugrim, and T. Nikolskaya.Computational prediction of human drug metabolism. Expert. Opin. Drug Metab. Toxicol. 1:303-324 (2005).
28. A. Endo. The origin of the statins. Int. Congr. Ser. 1262:3-8 (2004).
29. T. Walley, P. Folino-Gall, U. Schwabe, and E. van Ganse. Variation and increase in use of statins across Europe: data from administrative databases. Br. Med. J. 328:385-386 (2004).
30. B. Testa and J. M. Mayer. Hydrolysis in Drug and Prodrug Metabolism - Chemistry, Biochemistry and Enzymology, Wiley-VHCA, Zurich, 2003, pp. 493-495.
31. B. A. Hamelin and J. Turgeon. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. TIPS 19:26-37 (1998).
32. M. J. Kaufman. Rate and equilibrium constants for acid-catalyzed lactone hydrolysis of HMG-CoA reductase inhibitors. Int. J. Pharm. 66:97-106 (1990).
33. D. E. Duggan, I.-W. Chen, W. F. Bayne, R. A. Halpin, C. A. Duncan, M. S. Schwartz, R. J. Stubbs, and S. Vickers. The physiological disposition of lovastatin. Drug Metab. Dispos. 17:166-173 (1989).
34. H. Fujino, T. Saito, Y. Tsunenari, J. Kojima, and T. Sakaeda. Metabolic properties of the acid and lactone forms of HMC-CoA reductase inhibitors. Xenobiotica 34:961-971 (2004).
35. T. Prueksaritanont, B. Ma, X. Fang, R. Subramanian, J. Yu, and J. H. Lin. β-oxidation of simvastatin in mouse liver preparations. Drug Metab. Dispos. 29:1251-1255 (2001).
36. M. J. Garcia, R. F. Reinoso, A. Sanchez Navarrro, and J. R. Prous. Clinical pharmacokinetics of statins. Meth. Fin. Exp. Clin. Pharmacol. 25:457-481 (2003).
37. U. Christians, W. Jacobsen, and L. C. Floren. Metabolism of drug interactions of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors in transplant patients: are the statins mechanistically similar?. Pharmacol. Ther. 80:1-34 (1998).
38. D. Zhou, L. Afzelius, S. W. Grimm, T. B. Andersson, R. J. Zauhar, and I. Zamora. Comparison of methods for the prediction of the metabolic sites for CYP3A4-mediated metabolic reactios. Drug Metab. Dispos. 34:976-983 (2006).
39. G. Cruciani, R. Vianello, and I. Zamora. Prediction of site of metabolism in humans: case studies of cytochromes P450 2C9, 2D6 and 3A4. In B. Testa, S. Kraemer, H. Wunderli-Allenspach, and G. Folkers (eds.), Pharmacokinetic Profiling in Drug Research: Biological, Physicochemical and Computational Strategies, Wiley-VHCA, Zürich, 2005, pp. 367-379.
40. G. Cruciani, E. Carosati, B. De Boeck, K. Ethirajulu, C. Mackie, T. Howe, and R. Vianello. MetaSite: understanding metabolism in human cytochromes from the perspective of the chemist. J. Med. Chem. 48:6970-6979 (2005).
41. D. N. A. Boobbyer, P. J. Goodford, P. M. McWhinnie, and R. C. Wade. New hydrogen-bond potentials for use in determining energetically favorable binding sites on molecules of known structure. J. Med. Chem. 32:1083-1094 (1989).
42. P. J. Goodford. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem. 28:849-857 (1985).
43. R. C. Wade, K. J. Clark, and P. J. Goodford. Further development of hydrogen bond functions for use in determining energetically favorable binding sites on molecules of known structure. I. Ligand probe groups with the ability to form two hydrogen bonds. J. Med. Chem. 36:140-147 (1993).
44. R. C. Wade and P. J. Goodford. Further development of hydrogen bond functions for use in determining energetically favorable binding sites on molecules of known structure. II. Ligand probe groups with the ability to form more than two hydrogen bonds. J. Med. Chem. 36:148-156 (1993).
45. A. R. Leach, B. K. Shoichet, and C. E. Peishoff. Prediction of protein-ligand interactions. Docking and scoring: successes and gaps. J. Med. Chem. 49:5851-5855 (2006).
46. MOE, version 2005.06, 2005,. Chemical Computing Group, Montreal, Quebec Canada, http://www.chemcomp.com/.
47. T. A. Halgren. MMFF VI. MMFF94s option for energy minimization studies. J. Comput. Chem. 20:720-729 (1999).
48. Vega, version 2.0.5., 2006, http://www.ddl.unimi.it/.
49. G. Caron, G. Ermondi, A. Damiano, L. Novaroli, O. Tsinman, J. A. Ruell, and A. Avdeef. Ionization, lipophilicity, and molecular modeling to investigate permeability and other biological properties of amlodipine. Bioorg. Med. Chem.12:6107-6118 (2004).
50. D. Qiu, P. S. Shenkin, F. P. Hollinger, and W. C. Still. The GB/SA continuum model for solvation. A fast analytical method for the calculation of approximate born radii. J. Phys. Chem., A. 101:3005-3014 (1997).
51. T. Sakaeda, H. Fujino, C. Komoto, M. Kakumoto, J. Jin, K. Iwaki, K. Nishiguchi, T. Nakamura, N. Okamura, and K. Okumura. Effects of acid and lactone forms of eight HMG-CoA reductase inhibitors on CYP-mediated metabolism and MDR1-mediated transport. Pharm. Res. 23:506-512 (2006).
52. W. F. Trager. Principles of drug metabolism 1: redox reactions. In B. Testa and H. van de Waterbeemd (eds.), Comprehensive Medicinal Chemistry, 2nd Edition, Volume 5, Elsevier, Oxford, UK, 2006, pp. 87-132.
53. M. Boberg, R. Angerbauer, P. Fey, W. K. Kanhai, W. Karl, A. Kern, J. Ploschke, and M. Radtke. Metabolism of cerivastatin by human liver microsomes in vitro. Drug Metab. Dispos. 25 321-331 (1997).
54. T. Prueksaritanont, J. J. Zhao, B. Ma, B. A. Roadcap, C. Tang, Y. Qiu, L. Liu, J. H. Lin, P. G. Pearson, and T. A. Baillie. Mechanistic studies on metabolic interactions between gemfibrozil and statins. J. Pharmacol. Exp. Ther. 301:1042-1051 (2002).
55. M. Boberg, R. Angerbauer, W. K. Kanhai, W. Karl, A. Kern, M. Radtke, and W. Steinke. Biotransformation of cerivastatin inmice, rats, and dogs in vivo. Drug Metab. Dispos. 26:640-652 (1998).
56. W. Jacobsen, G. Kirchner, K. Hallensleben, L. Mancinelli, M. Deters, I. Hackbarth, L. Z. Benet, K.-F. Sewing, and U. Christians. Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA-reductase inhibitors lovastatin and pravastatin in the liver. Drug Metab. Dispos. 27:173-179 (1998).
57. B. Testa. The Metabolism of Drugs and Other Xenobiotics - Biochemistry of Redox Reactions, Academic, London, UK, 1995.
58. H. Fujino, I. Yamada, S. Shimada, M. Yoneda, and J. Kojima. Metabolic fate of pitavastatin, a new inhibitor of HMG-CoA reductase: human UDP-glucuronosyltansferase enzymes involved in lactonization. Xenobiotica 33:27-41 (2003).
59. B. Testa and S. Kraemer. The biochemistry of drug metabolism. An introduction. Part 2. Redox reactions and their enzymes. Chem. Biodivers. (2007) (in press).
60. D. W. Everett, T. J. Chando, G. C. Didonato, S. M. Singhvi, H. Y. Pan, and S. H. Weinstein. Biotransformation of pravastatin sodium in humans. Drug Metab. Dispos. 19:740-748 (1991).
61. J. Cejka, B. Kratochvil, I. Cisarova, and A. Jegorov. Simvastatin. Acta Crystallogr. C59:o428-o430 (2003).
62. F. H. Allen. The Cambridge structural database: a quarter of a million crystal structures and rising. Acta Crystallogr. B58:380-388 (2002).
63. R. Subramanian, X. Fang, and T. Prueksaritanont. Structural characterization of in vivo rat glutathione adducts and a hydroxylated metabolite of simvastatin hydroxy acid. Drug Metab. Dispos. 30:225-230 (2006).
64. S. Vickers, C. A. Duncan, I.-W. Chen, A. Rosegay, and D. E. Duggan. Metabolic disposition studies of simvastatin, a cholesterol-lowering product. Drug Metab. Dispos. 18:138-145 (1990).
65. S. Vickers and C. A. Duncan. In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG-CoA reductase. Drug Metab. Dispos. 18:476-483 (1990).