title: Rate of onset of inhibition of gut-wall and hepatic CYP3A by clarithromycin.
abstract: OBJECTIVE
  To determine the extent and time-course of hepatic and intestinal cytochrome P450 3A (CYP3A) inactivation due to the mechanism-based inhibitor clarithromycin.
  
  
  METHODS
  Intestinal and hepatic CYP3A inhibition was examined in 12 healthy volunteers following the administration of single and multiple doses of oral clarithromycin (500 mg). Intestinal biopsies were obtained under intravenous midazolam sedation at baseline and after the first dose, on days 2-4, and on days 6-8 of the clarithromycin treatment. The formation of 1'-hydroxymidazolam in biopsy tissue and the serum 1'-hydroxymidazolam:midazolam ratio were indicators of intestinal and hepatic CYP3A activity, respectively.
  
  
  RESULTS
  Intestinal CYP3A activity decreased by 64 % (p = 0.0029) following the first dose of clarithromycin, but hepatic CYP3A activity did not significantly decrease. Repeated dosing of clarithromycin caused a significant decrease in hepatic CYP3A activity (p = 0.005), while intestinal activity showed little further decline. The CYP3A5 or CYP3A4*1B genotype were unable to account for inter-individual variability in CYP3A activity.
  
  
  CONCLUSIONS
  Following the administration of clarithromycin, the onset of hepatic CYP3A inactivation is delayed compared to that of intestinal CYP3A. The time-course of drug-drug interactions due to clarithromycin will vary with the relative contribution of intestinal and hepatic CYP3A to the clearance and bioavailability of a victim substrate.
authors: Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Sara K
authors: SK
authors: Quinney
authors: Srikar R
authors: SR
authors: Malireddy
authors: Raj
authors: R
authors: Vuppalanchi
authors: Mitchell A
authors: MA
authors: Hamman
authors: Naga
authors: N
authors: Chalasani
authors: J Christopher
authors: JC
authors: Gorski
authors: Stephen D
authors: SD
authors: Hall
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D001706:Biopsy; D001711:Biotransformation; D017291:Clarithromycin / Q000008:administration & dosage*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004334:Drug Administration Schedule; D004386:Duodenum / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D008875:Middle Aged; D010641:Phenotype; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; C040081:1-hydroxymethylmidazolam; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin; D008874:Midazolam