Abstract
In an in vitro study, we compared the cytochrome P450 (CYP)-dependent metabolism and drug interactions of the acid and lactone forms of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor atorvastatin. Metabolism of atorvastatin acid and lactone by human liver microsomes resulted in para-hydroxy andortho-hydroxy metabolites. Both substrates were metabolized mainly by CYP3A4 and CYP3A5. Atorvastatin lactone had a significantly higher affinity to CYP3A4 than the acid (Km: para-hydroxy atorvastatin, 25.6 ± 5.0 μM; para-hydroxy atorvastatin lactone, 1.4 ± 0.2 μM;ortho-hydroxy atorvastatin, 29.7 ± 9.4 μM; andortho-hydroxy atorvastatin lactone, 3.9 ± 0.2 μM). Compared with atorvastatin acid, CYP-dependent metabolism of atorvastatin lactone to its para-hydroxy metabolite was 83-fold higher [formation CLint(Vmax/Km): lactone 2949 ± 3511 versus acid 35.5 ± 48.1 μl · min−1 · mg−1] and to itsortho-hydroxy metabolite was 20-fold higher (CLint: lactone 923 ± 965 versus acid 45.8 ± 59.1 μl · min−1 · mg−1). Atorvastatin lactone inhibited the metabolism of atorvastatin acid by human liver microsomes with an inhibition constant (Ki) of 0.9 μM while theKi for inhibition of atorvastatin by atorvastatin lactone was 90 μM. Binding free energy calculations of atorvastatin acid and atorvastatin lactone complexed with CYP3A4 revealed that the smaller desolvation energy of the neutral lactone compared with the anionic acid is the dominant contribution to the higher binding affinity of the lactone rather than an entropy advantage. Because atorvastatin lactone has a significantly higher metabolic clearance and the lactone is a strong inhibitor of atorvastatin acid metabolism, it can be expected that metabolism of the lactone is the relevant pathway for atorvastatin elimination and drug interactions. We hypothesize that most of the open acid metabolites present in human plasma are generated by interconversion of lactone metabolites.
Footnotes
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Send reprint requests to: Uwe Christians, Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143-0446. E-mail: uwec{at}itsa.ucsf.edu
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W.J. and L.Z.B. were supported in part by National Institutes of Health Grant CA72006; B.K. was supported by a research scholarship of the German Academic Exchange Service (DAAD); G.I.K. and K.F.S. by the Deutsche Forschungsgemeinschaft, Grant SFB265 A7; P.A.K. by National Institutes of Health Grant GM29072; and U.C. by the Deutsche Forschungsgemeinschaft, Grant Ch 95/6-2.
- Abbreviations used are::
- HMG-CoA
- 3-hydroxy-3-methylglutaryl-coenzyme A
- AUC
- area under the curve
- CYP
- cytochrome P450
- HOMO
- highest occupied molecular orbital
- LC
- liquid chromatography
- MD
- molecular dynamics
- MM/PBSA
- molecular mechanics/Poisson-Boltzmann surface area
- MS
- mass spectrometry
- QM/MM
- quantum mechanics/molecular mechanics
- Received April 10, 2000.
- Accepted July 27, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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