Dalbøge, C S3; Nielsen, X C3; Dalhoff, K3; Alffenaar, J W3; Duno, M3; Buchard, A4; Uges, D R A3; Jensen, A G3; Jürgens, G3; Pressler, T3; Johansen, H K3; Høiby, N5
1 Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet3 unknown4 Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health and Medical Sciences, Københavns Universitet5 Department of Immunology and Microbiology, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, Københavns Universitet
BACKGROUND: To investigate the correlation between CYP3A4/5 activity and clarithromycin metabolism, and between CYP3A activity and CYP3A genotype. METHODS: This is an open-label, prospective pharmacokinetic study evaluating CYP3A activity using The Erythromycin Breath Test. Eight blood samples were collected within 12h after clarithromycin 500 mg was administered orally. The clarithromycin concentrations were measured by liquid chromatography-tandem mass spectrometry. AUC, Tmax and Cmax were calculated. Selected Single Nucleotide polymorphisms in CYP3A4/5 genes were assessed by PCR and single base extension. RESULTS: Twenty-one chronically infected patients were included. An 8-fold variation in the CYP3A4 activity, 10-fold variation in AUC for clarithromycin (median 881 μg/mL × min), and a 16-fold variation in Cmax for clarithromycin (median 3.4 μg/mL) were found. A linear correlation between the CYP3A4-activity and clarithromycin metabolism was demonstrated (P < 0.05). CONCLUSION: The large variation in the clarithromycin pharmacokinetics in cystic fibrosis patients may cause treatment failure. The Erythromycin Breath Test could be valuable in identifying cystic fibrosis patients in risk of treatment failure/drug toxicity.
Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society, 2014, Vol 13, Issue 2, p. 179-85
Adult; Anti-Bacterial Agents; Area Under Curve; Biotransformation; Breath Tests; Chromatography, Liquid; Clarithromycin; Cystic Fibrosis; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Female; Genetic Association Studies; Humans; Male; Polymorphism, Single Nucleotide; Prospective Studies; Risk Assessment; Tandem Mass Spectrometry; Treatment Failure; Journal Article; Research Support, Non-U.S. Gov't