title: Pharmacokinetic variability of clarithromycin and differences in CYP3A4 activity in patients with cystic fibrosis.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, Juliane Maries Vej 22, 2100 Copenhagen Ø, Denmark. Electronic address: christinadalboege@gmail.com.
authors.forename: C S
authors.initials: CS
authors.lastname: Dalbøge
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, Juliane Maries Vej 22, 2100 Copenhagen Ø, Denmark; Department of Clinical Microbiology, Slagelse Hospital, Ingemannsvej 18, 4200 Slagelse, Denmark.
authors.forename: X C
authors.initials: XC
authors.lastname: Nielsen
authors.affiliation: Department of Clinical Pharmacology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Dalhoff
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical and Hospital Pharmacy, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: Alffenaar
authors.affiliation: Department of Clinical Genetics, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark.
authors.forename: M
authors.initials: M
authors.lastname: Duno
authors.affiliation: Section of Forensic Genetics, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Frederik V's Vej 11, 2100 Copenhagen Ø, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Buchard
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Clinical and Hospital Pharmacy, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: D R A
authors.initials: DR
authors.lastname: Uges
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, Juliane Maries Vej 22, 2100 Copenhagen Ø, Denmark.
authors.forename: A G
authors.initials: AG
authors.lastname: Jensen
authors.affiliation: Department of Clinical Pharmacology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Jürgens
authors.affiliation: Department of Pediatrics, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø, Denmark.
authors.forename: T
authors.initials: T
authors.lastname: Pressler
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, Juliane Maries Vej 22, 2100 Copenhagen Ø, Denmark.
authors.forename: H K
authors.initials: HK
authors.lastname: Johansen
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, Juliane Maries Vej 22, 2100 Copenhagen Ø, Denmark; Institute of International Health, Immunology, and Microbiology, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
authors.forename: N
authors.initials: N
authors.lastname: Høiby
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001711:Biotransformation / Q000235:genetics; D001944:Breath Tests / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D017291:Clarithromycin / Q000008:administration & dosage / Q000493:pharmacokinetics; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000175:diagnosis / Q000235:genetics / Q000517:prevention & control; D004917:Erythromycin; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018570:Risk Assessment; D053719:Tandem Mass Spectrometry / Q000379:methods; D017211:Treatment Failure
chemical_list: D000900:Anti-Bacterial Agents; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin
keywords: AUC; Cytochrome P450; ERMBT; SNPs