Pharmaceutical Research

, Volume 24, Issue 3, pp 480–501 | Cite as

Predicting the Oxidative Metabolism of Statins: An Application of the MetaSite® Algorithm

Research Paper

Abstract

Purpose

This study was undertaken to examine the MetaSite algorithm by comparing its predictions with experimentally characterized metabolites of statins produced by cytochromes P450 (CYPs).

Methods

Seven statins were investigated, namely atorvastatin, cerivastatin, fluvastatin, pitavastatin and pravastatin which are (or were) used in their active hydroxy-acid form, and lovastatin and simvastatin which are used as the lactone prodrug. But given the fast lactone-hydroxy-acid equilibrium undergone by statins, both forms were investigated for each of the seven drugs. The MetaSite version 2.5.3 used here contains the homology 3D-models of CYP1A2, CYP2C19, CYP2C9, CYP2D6 and CYP3A4. In addition, we also used the crystallographic 3D-structure of human CYP2C9 and CYP3A4. To allow a better interpretation of results, the probability function P SM i calculated by MetaSite (namely the probability of atom i to be a site of metabolism) was explicitly decomposed into its two components, namely a recognition score Ei (the accessibility of atom i) and the chemical reactivity Ri of atom i toward oxidation reactions.

Results

The current version of MetaSite is known to work best with prior experimental knowledge of the cytochrome(s) P450 involved. And indeed, experimentally confirmed sites of oxidation were correctly given a high priority by MetaSite. In particular 77% of correct predictions (including false positive but, as discussed, this is not necessarily a shortcoming) were obtained when considering the first five metabolites indicated by MetaSite.

Conclusion

To the best of our knowledge, this is the first independent report on the software. It is expected to contribute to the development of improved versions, but above all it demonstrates that the usefulness of such softwares critically depends on human experts.

Key words

in silico metabolism prediction MetaSite molecular fields statins 

Notes

Acknowledgements

GC and GE are indebted to the University of Turin for financial support. The authors thank Silvia Tonelli for the preliminary work carried out during her undergraduate period of study. Molecular Discovery is also acknowledged for a free license and technical support.

Supporting Information Available: Corresponding atoms in the lactone and hydroxy-acid forms together with the complete lists of PSMi, E i and R i data for all investigated compounds.

Supplementary material

11095_2006_9199_MOESM1_ESM.doc (56 kb)
Table S1 Automatic numbering: the correspondence between lactones and open forms are shown (DOC 57.344 KB).
11095_2006_9199_MOESM2_ESM.doc (44 kb)
Table S2 Atorvastatin lactone: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 288.768 KB).
11095_2006_9199_MOESM3_ESM.doc (94 kb)
Table S3 Atorvastatin: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 96.256 KB).
11095_2006_9199_MOESM4_ESM.doc (88 kb)
Table S4 Cerivastatin lactone: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 89.600 KB).
11095_2006_9199_MOESM5_ESM.doc (92 kb)
Table S5 Cerivastatin: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 93.696 KB).
11095_2006_9199_MOESM6_ESM.doc (76 kb)
Table S6 Fluvastatin lactone: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 78.336 KB).
11095_2006_9199_MOESM7_ESM.doc (80 kb)
Table S7 Fluvastatin: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 81.920 KB).
11095_2006_9199_MOESM8_ESM.doc (92 kb)
Table S8 Lovastatin: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 93.696 KB).
11095_2006_9199_MOESM9_ESM.doc (95 kb)
Table S9 Lovastatin open form: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 97.280 KB).
11095_2006_9199_MOESM10_ESM.doc (74 kb)
Table S10 Pitavastatin lactone: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 75.776 KB).
11095_2006_9199_MOESM11_ESM.doc (78 kb)
Table S11 Pitavastatin: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 79.872 KB).
11095_2006_9199_MOESM12_ESM.doc (90 kb)
Table S12 Pravastatin lactone: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 92.672 KB).
11095_2006_9199_MOESM13_ESM.doc (92 kb)
Table S13 Pravastatin: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 94.720 KB).
11095_2006_9199_MOESM14_ESM.doc (94 kb)
Table S14 Simvastatin: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 96.256 KB).
11095_2006_9199_MOESM15_ESM.doc (98 kb)
Table S15 Simvastatin open form: the probability PSM, the recognition score Ei and the chemical reactivity Ri (DOC 100.352 KB).

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Dipartimento di Scienza e Tecnologia del FarmacoTorinoItaly
  2. 2.Pharmacy DepartmentUniversity HospitalLausanne-CHUVSwitzerland

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