Document Detail

Effect of itraconazole on the pharmacokinetics of rosuvastatin.
MedLine Citation:
PMID:  12709722     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Rosuvastatin is a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. Itraconazole, an inhibitor of cytochrome P450 (CYP) 3A4 and the transport protein P-glycoprotein, is known to interact with other HMG-CoA reductase inhibitors. The current trials aimed to examine in vivo the effect of itraconazole on the pharmacokinetics of rosuvastatin. METHODS: Two randomized, double-blind, placebo-controlled, 2-way crossover trials were performed. Healthy male volunteers (trial A, n = 12; trial B, n = 14) received itraconazole, 200 mg, or placebo once daily for 5 days; on day 4, 10 mg (trial A) or 80 mg (trial B) of rosuvastatin was coadministered. Plasma concentrations of rosuvastatin, rosuvastatin-lactone (trial A only), and active and total HMG-CoA reductase inhibitors were measured up to 96 hours after dosing. RESULTS: After coadministration with itraconazole, the rosuvastatin geometric least-square mean for the treatment ratio was increased by 39% for AUC(0-ct) (area under the rosuvastatin plasma concentration-time curve from time 0 to the last common time at which quantifiable concentrations were obtained for both treatments within a volunteer in trial A) and by 28% for AUC(0-t) (area under the rosuvastatin plasma concentration-time curve from time 0 to the time of the last quantifiable concentration in trial B), with the treatment ratio for maximum observed plasma drug concentration increased by 36% in trial A and 15% in trial B compared with placebo. For trial A (but not for trial B), the upper boundary of the 90% confidence interval for the treatment ratios fell outside the preset limits (0.7-1.43). The 95% confidence intervals for all treatment ratios (except maximum observed plasma drug concentration in trial B) did not include 1. These results indicate that itraconazole produces a modest increase in plasma concentrations of rosuvastatin. Rosuvastatin accounted for the majority of the circulating active HMG-CoA reductase inhibitors (> or =87%) and most of the total inhibitors (> or =75%). CONCLUSIONS: Itraconazole produced modest increases in rosuvastatin plasma concentrations, which are unlikely to be of clinical relevance. The results support previous in vitro metabolism findings that CYP3A4 plays a minor role in the limited metabolism of rosuvastatin.
Kelvin J Cooper; Paul D Martin; Aaron L Dane; Mike J Warwick; Dennis W Schneck; Mireille V Cantarini
Publication Detail:
Type:  Clinical Trial; Journal Article; Randomized Controlled Trial    
Journal Detail:
Title:  Clinical pharmacology and therapeutics     Volume:  73     ISSN:  0009-9236     ISO Abbreviation:  Clin. Pharmacol. Ther.     Publication Date:  2003 Apr 
Date Detail:
Created Date:  2003-04-23     Completed Date:  2003-05-07     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  0372741     Medline TA:  Clin Pharmacol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  322-9     Citation Subset:  AIM; IM    
AstraZeneca, Macclesfield, Cheshire, United Kingdom.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Area Under Curve
Cross-Over Studies
Double-Blind Method
Drug Interactions
Fluorobenzenes / blood,  pharmacokinetics*
Itraconazole / pharmacology*
Middle Aged
Reg. No./Substance:
0/Fluorobenzenes; 0/Pyrimidines; 0/Sulfonamides; 287714-41-4/rosuvastatin; 84625-61-6/Itraconazole

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

Previous Document:  Calcitonin gene-related peptide: exploring its vasodilating mechanism of action in humans.
Next Document:  Pharmacokinetics of fluoxetine and norfluoxetine in pregnancy and lactation.