Document Detail

Clinical pharmacokinetics of cerivastatin.
MedLine Citation:
PMID:  10976657     Owner:  NLM     Status:  MEDLINE    
Cerivastatin sodium, a novel statin, is a synthetic, enantiomerically pure, pyridine derivative that effectively reduces serum cholesterol levels at microgram doses. Cerivastatin is readily and completely absorbed from the gastrointestinal tract, with plasma concentrations reaching a peak 2 to 3 hours postadministration followed by a monoexponential decay with an elimination half-life (t1/2beta) of 2 to 3 hours. Cerivastatin pharmacokinetics are linear: maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) are proportional to the dose over the range of 0.05 to 0.8 mg. No accumulation is observed on repeated administration. Cerivastatin interindividual variability is described by coefficients of variation of approximately 30 to 40% for its primary pharmacokinetic parameters AUC, Cmax and t1/2beta. The mean absolute oral bioavailability of cerivastatin is 60% because of presystemic first-pass effects. Its pharmacokinetics are not influenced by concomitant administration of food nor by the time of day at which the dose is given. Age, gender, ethnicity and concurrent disease also have no clinically significant effects. Cerivastatin is highly bound to plasma proteins (>99%). The volume of distribution at steady state of about 0.3 L/kg indicates that the drug penetrates only moderately into tissue; conversely, preclinical studies have shown a high affinity for liver tissue, the target site of action. Cerivastatin is exclusively cleared via metabolism. No unchanged drug is excreted. Cerivastatin is subject to 2 main oxidative biotransformation reactions: demethylation of the benzylic methyl ether moiety leading to the metabolite M-1 [catalysed by cytochrome P450 (CYP) 2C8 and CYP3A4] and stereoselective hydroxylation of one methyl group of the 6-isopropyl substituent leading to the metabolite M-23 (catalysed by CYP2C8). The product of the combined biotransformation reactions is a secondary minor metabolite, M-24, not detectable in plasma. All 3 metabolites are active inhibitors of hydroxymethylglutaryl-coenzyme A reductase with a similar potency to the parent drug. Approximately 70% of the administered dose is excreted as metabolites in the faeces, and 30% in the urine. Metabolism by 2 distinct CYP isoforms renders cerivastatin relatively resistant to interactions arising from inhibition of CYP. If one of the pathways is blocked, cerivastatin can be effectively metabolised by the alternative route. In addition, on the basis of in vitro investigations, there is no evidence for either cerivastatin or its metabolites having any inducing or inhibitory activity on CYP. The apparent lack of any clinically relevant interactions with a variety of drugs commonly used by patients in the target population supports this favourable drug-drug interaction profile.
W Mück
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Clinical pharmacokinetics     Volume:  39     ISSN:  0312-5963     ISO Abbreviation:  Clin Pharmacokinet     Publication Date:  2000 Aug 
Date Detail:
Created Date:  2001-01-04     Completed Date:  2001-01-04     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  7606849     Medline TA:  Clin Pharmacokinet     Country:  NEW ZEALAND    
Other Details:
Languages:  eng     Pagination:  99-116     Citation Subset:  IM    
Institute of Clinical Pharmacology, Bayer AG, Pharma Research Center, Wuppertal, Germany.
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MeSH Terms
Cytochrome P-450 CYP3A
Cytochrome P-450 Enzyme System / antagonists & inhibitors*
Drug Interactions / physiology
Hydroxymethylglutaryl-CoA Reductase Inhibitors / chemistry,  pharmacokinetics*,  therapeutic use
Hypercholesterolemia / drug therapy,  metabolism*
Mixed Function Oxygenases / antagonists & inhibitors*
Pyridines / chemistry,  pharmacokinetics*,  therapeutic use
Reg. No./Substance:
0/Hydroxymethylglutaryl-CoA Reductase Inhibitors; 0/Pyridines; 0/cerivastatin; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC protein, human; EC protein, human; EC P-450 CYP3A

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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