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Titolo:
INFLUENCE OF ERYTHROMYCIN PRE-TREATMENT AND CO-TREATMENT ON SINGLE-DOSE PHARMACOKINETICS OF THE HMG-COA-REDUCTASE INHIBITOR CERIVASTATIN
Autore:
MUCK W; OCHMANN K; ROHDE G; UNGER S; KUHLMANN J;
Indirizzi:
BAYER AG,CLIN PHARMACOL,APRATHER WEG,BLDG 405-V D-42096 WUPPERTAL GERMANY BAYER AG,BIOMETRY D-42096 WUPPERTAL GERMANY
Titolo Testata:
European Journal of Clinical Pharmacology
fascicolo: 6, volume: 53, anno: 1998,
pagine: 469 - 473
SICI:
0031-6970(1998)53:6<469:IOEPAC>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
CORONARY-HEART-DISEASE; CARDIAC TRANSPLANTATION; DRUG-INTERACTION; LOVASTATIN; RHABDOMYOLYSIS; PLASMA; ITRACONAZOLE; CYCLOSPORINE; CHOLESTEROL; PRAVASTATIN;
Keywords:
CERIVASTATIN; CYTOCHROME P450 3A4 INHIBITION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
24
Recensione:
Indirizzi per estratti:
Citazione:
W. Muck et al., "INFLUENCE OF ERYTHROMYCIN PRE-TREATMENT AND CO-TREATMENT ON SINGLE-DOSE PHARMACOKINETICS OF THE HMG-COA-REDUCTASE INHIBITOR CERIVASTATIN", European Journal of Clinical Pharmacology, 53(6), 1998, pp. 469-473

Abstract

Objective: Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation MI; hydroxylation M23) and subsequent biliary/renalexcretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated. Methods: Twelve healthy young male subjects received single oral doses of 300 mu g cerivastatin alone or on the 4th day of a 4-day pre-and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatographyassays. Results: Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre-and cotreatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (C-max) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUG) of 21%, time to peak (t(max)) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing,the mean AUC of M23 exhibited an increase of approximately 60%. The respective C-max results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1). Conclusions:Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 mu g, resulting in a slightly increased exposureof the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochromeP450 isozymes are differently involved in the metabolic pathways of cerivastatin.

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Documento generato il 22/01/20 alle ore 18:59:08