NDLI: Effect of cytochrome P450 3A5 genotype on atorvastatin pharmacokinetics and its interaction with clarithromycin.

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Effect of cytochrome P450 3A5 genotype on atorvastatin pharmacokinetics and its interaction with clarithromycin.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Shin, Jaekyu Pauly, Daniel F. Pacanowski, Michael A. Langaee, Taimour Frye, Reginald F. Johnson, Julie A.
Description	Country affiliation: United States Author Affiliation: Shin J ( College of Pharmacy and Center for Pharmacogenomics, University of Florida, Health Science Center, Gainesville, FL 32610-0486, USA.)
Abstract	Abstract Study Objective. To assess the effects of the cytochrome P450 (CYP) 3A genotype, CYP3A5, on atorvastatin pharmacokinetics and its interaction with clarithromycin. Design. Prospective, two-phase, randomized-sequence, open-label pharmacokinetic study. Setting. Clinical research center at a teaching hospital. Subjects. Twenty-three healthy volunteers who were screened for genotype: 10 subjects carried the CYP3A5*1 allele (expressors) and 13 subjects did not (nonexpressors). Intervention. In one phase, subjects received a single oral dose of atorvastatin 20 mg. In the other phase, subjects received clarithromycin 500 mg twice/day for 5 days; on day 4 after the morning dose, subjects also received a single oral dose of atorvastatin 20 mg. All subjects participated in both phases of the study, which were separated by at least 14 days. Measurements and Main Results. Pharmacokinetic parameters of both forms of atorvastatin-atorvastatin acid and atorvastatin lactone-were compared between CYP3A5 expressors and nonexpressors, both in the absence and presence of clarithromycin, a strong CYP3A inhibitor. The acid form is pharmacologically active, and the lactone form has been associated with the atorvastatin's muscle-related adverse effects. Atorvastatin acid exposure did not differ significantly between CYP3A5 genotype groups. When subjects had not received clarithromycin pretreatment, the area under the concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) of atorvastatin lactone was 36% higher in nonexpressors than in expressors (median 47.6 ngâ¢hr/ml [interquartile range (IQR) 37.8-64.3 ngâ¢hr/ml] vs 34.9 ngâ¢hr/ml [IQR 21.6-42.2 ngâ¢hr/ml], p=0.038). After clarithromycin pretreatment, changes in the pharmacokinetic parameters of atorvastatin acid and lactone were not significantly different between the nonexpressors versus the expressors; however, the increase in the AUC(0-∞) of atorvastatin lactone was 37% greater in expressors than in nonexpressors (geometric mean ± SD 3.59 ± 0.57 vs 2.62 ± 0.35, p=0.049). Conclusion. Our data suggest that the CYP3A5 genotype has minimal effects on the pharmacokinetic parameters of atorvastatin and its interaction with clarithromycin; these effects are unlikely to be clinically significant.
File Format	HTM / HTML
ISSN	02770008
e-ISSN	18759114
DOI	10.1592/phco.31.10.942
Journal	Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy
Issue Number	10
Volume Number	31
Language	English
Publisher	Wiley-Blackwell
Publisher Date	2011-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Pharmacology Clarithromycin Pharmacology Cytochrome P-450 Cyp3a Inhibitors Cytochrome P-450 Cyp3a Genetics Heptanoic Acids Pharmacokinetics Hydroxymethylglutaryl-coa Reductase Inhibitors Pyrroles Alleles Atorvastatin Calcium Blood Drug Interactions Genotype Administration & Dosage Chemistry Prospective Studies Randomized Controlled Trial
Content Type	Text
Resource Type	Article
Subject	Pharmacology (medical)

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