DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Black, A. E.
Right arrow Articles by Woolf, T. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Black, A. E.
Right arrow Articles by Woolf, T. F.

Vol. 26, Issue 8, 755-763, August 1998

Metabolism and Excretion Studies in Mouse After Single and Multiple Oral Doses of the 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitor Atorvastatin

Ann E. Black, Michael W. Sinz, Roger N. Hayes, and Thomas F. Woolf

Department of Pharmacokinetics and Drug Metabolism, Parke-Davis Pharmaceutical Research Company

Atorvastatin, [(R-(R,R)]-2-(4-fluorophenyl)-beta ,delta -dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenyl-amino)carbonyl]-1H-pyrrole-1-heptanoic acid calcium salt (CI-981, AT), is a second generation 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor approved for clinical use as a cholesterol lowering agent. The disposition and metabolism of AT, including potential CYP450 induction, was investigated in mice administered an oral dose of [14C]AT (free acid) on study days 1 and 14. Peak plasma radioactivity concentrations occurred 1 hr postdose after both single- and multiple-dose administration and declined rapidly thereafter. Total plasma radioactivity levels in mice receiving the multiple dose were approximately 50% of levels observed after single-dose administration. Plasma metabolic profiles, which provided evidence of extensive metabolism, remained similar. Feces was the major route of AT-derived radioactivity elimination. Fecal profiles showed extensive metabolism with qualitatively similar profiles after single- and multiple-dose administration; however, quantitative differences were apparent. Metabolites identified in plasma and feces include hydroxylated, beta -oxidized, and unsaturated derivatives of AT. Most metabolites had undergone beta -oxidation. In mice receiving multiple 1 mg/kg doses of AT, no effect on spectral P450 concentration was found, and only a minor increase was observed at the 200 mg/kg dose level. Catalytic activities of CYP4501A, -2B, and -3A were not significantly affected; CYP4A activity decreased in a dose-dependent manner. Administration of multiple doses resulted in lower systemic plasma levels of total AT-derived radioactivity not readily explained by these studies. In mice, the majority of metabolites are formed primarily through the beta -oxidation pathway.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 PDA J Pharm Sci TechnolHome page
C. R. Palem, S. Patel, and V. B. Pokharkar
Solubility and Stability Enhancement of Atorvastatin by Cyclodextrin Complexation
PDA J. Pharm. Sci. Technol., May 1, 2009; 63(3): 217 - 225.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
R. C. Bucelli, E. A. Gonsiorek, W.-Y. Kim, D. Bruun, R. A. Rabin, D. Higgins, and P. J. Lein
Statins Decrease Expression of the Proinflammatory Neuropeptides Calcitonin Gene-Related Peptide and Substance P in Sensory Neurons
J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1172 - 1180.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
W. Sun, T.-S. Lee, M. Zhu, C. Gu, Y. Wang, Y. Zhu, and J. Y-J. Shyy
Statins Activate AMP-Activated Protein Kinase In Vitro and In Vivo
Circulation, December 12, 2006; 114(24): 2655 - 2662.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
U. Landmesser, N. Engberding, F. H. Bahlmann, A. Schaefer, A. Wiencke, A. Heineke, S. Spiekermann, D. Hilfiker-Kleiner, C. Templin, D. Kotlarz, et al.
Statin-Induced Improvement of Endothelial Progenitor Cell Mobilization, Myocardial Neovascularization, Left Ventricular Function, and Survival After Experimental Myocardial Infarction Requires Endothelial Nitric Oxide Synthase
Circulation, October 5, 2004; 110(14): 1933 - 1939.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
O. Aktas, S. Waiczies, A. Smorodchenko, J. Dorr, B. Seeger, T. Prozorovski, S. Sallach, M. Endres, S. Brocke, R. Nitsch, et al.
Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells through Atorvastatin
J. Exp. Med., March 17, 2003; 197(6): 725 - 733.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. Prueksaritanont, R. Subramanian, X. Fang, B. Ma, Y. Qiu, J. H. Lin, P. G. Pearson, and T. A. Baillie
Glucuronidation of Statins in Animals and Humans: A Novel Mechanism of Statin Lactonization
Drug Metab. Dispos., May 1, 2002; 30(5): 505 - 512.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
T. Prueksaritanont, B. Ma, X. Fang, R. Subramanian, J. Yu, and J. H. Lin
beta -Oxidation of Simvastatin in Mouse Liver Preparations
Drug Metab. Dispos., October 1, 2001; 29(10): 1251 - 1255.
[Abstract] [Full Text] [PDF]

Home page
 Drug Metab. Dispos.Home page
A. E. Black, R. N. Hayes, B. D. Roth, P. Woo, and T. F. Woolf
Metabolism and Excretion of Atorvastatin in Rats And Dogs
Drug Metab. Dispos., August 1, 1999; 27(8): 916 - 923.
[Abstract] [Full Text]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1998 by the American Society for Pharmacology and Experimental Therapeutics.