Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis
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Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis. / Dalbøge, C S; Nielsen, X C; Dalhoff, K; Alffenaar, J W; Duno, M; Buchard, A; Uges, D R A; Jensen, A G; Jürgens, G; Pressler, T; Johansen, H K; Høiby, N.
In: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society, Vol. 13, No. 2, 03.2014, p. 179-85.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis
AU - Dalbøge, C S
AU - Nielsen, X C
AU - Dalhoff, K
AU - Alffenaar, J W
AU - Duno, M
AU - Buchard, A
AU - Uges, D R A
AU - Jensen, A G
AU - Jürgens, G
AU - Pressler, T
AU - Johansen, H K
AU - Høiby, N
N1 - © 2013.
PY - 2014/3
Y1 - 2014/3
N2 - 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.
AB - 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.
KW - Adult
KW - Anti-Bacterial Agents
KW - Area Under Curve
KW - Biotransformation
KW - Breath Tests
KW - Chromatography, Liquid
KW - Clarithromycin
KW - Cystic Fibrosis
KW - Cytochrome P-450 CYP3A
KW - Drug-Related Side Effects and Adverse Reactions
KW - Erythromycin
KW - Female
KW - Genetic Association Studies
KW - Humans
KW - Male
KW - Polymorphism, Single Nucleotide
KW - Prospective Studies
KW - Risk Assessment
KW - Tandem Mass Spectrometry
KW - Treatment Failure
U2 - 10.1016/j.jcf.2013.08.008
DO - 10.1016/j.jcf.2013.08.008
M3 - Journal article
C2 - 24035278
VL - 13
SP - 179
EP - 185
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
SN - 1569-1993
IS - 2
ER -
ID: 136496982