title: Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol.
abstract: OBJECTIVE
  A 7-day triple therapy with lansoprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for eradication of Helicobacter pylori. Because clarithromycin is a potent inhibitor of cytochrome P450 (CYP) 3A, we investigated whether the standard triple therapy with clarithromycin would elicit clinically relevant CYP3A inhibition and alter CYP3A-mediated lansoprazole disposition in H pylori-positive patients.
  
  
  METHODS
  Twenty H pylori-positive patients with peptic ulcer disease were randomly assigned to 2 groups: One group received 200 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days; the other group received 400 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days. Ten healthy control subjects received 30 mg lansoprazole and 750 mg amoxicillin at 8 am and 8 pm for 7 days but did not receive clarithromycin. Urine samples were collected for 3 hours (from 8 am to 11 am) for urinary 6beta-hydroxycortisol and cortisol assay, and midpoint (at 9:30 am) plasma samples for cortisol assay were obtained from all participants before the drug therapy (day 0) and on day 7. In vivo CYP3A activity was assessed by the partial cortisol clearance by means of the formation of 6beta-hydroxycortisol (CL(cortisol-->6beta-hydroxycortisol)) and the urinary 6beta-hydroxycortisol/cortisol ratio. Additional plasma samples for lansoprazole, 5-hydroxylansoprazole, and lansoprazole sulfone assay were obtained at 11 am on day 7.
  
  
  RESULTS
  The groups of patients given 400 and 800 mg/day clarithromycin for H pylori eradication therapy showed 39% (from 2.20 +/- 1.29 to 1.35 +/- 0.88 mL/min [day 0 versus 7, mean +/- SD]; P <.05) and 68% (2.40 +/- 1.22 to 0.76 +/- 0.51 mL/min; P <.05) reductions in CL(cortisol-->6beta-hydroxycortisol), respectively. In contrast, the control subjects given lansoprazole and amoxicillin without clarithromycin showed no significant changes in CL(cortisol-->6beta-hydroxycortisol). The urinary 6beta-hydroxycortisol/cortisol ratio also decreased significantly (P <.05) in the patient groups but not in the control subjects. The mean 3-hour plasma lansoprazole levels elevated in proportion to the doses of clarithromycin: 385 +/- 338 ng/mL for the control subjects, 696 +/- 797 ng/mL for the H pylori-positive patients given 400 mg/day clarithromycin, and 947 +/- 806 ng/mL for the H pylori-positive patients given 800 mg/day clarithromycin (P <.05 versus the control subjects). No significant differences were observed among the groups in the mean plasma ratios of 5-hydroxylansoprazole or lansoprazole sulfone to lansoprazole.
  
  
  CONCLUSIONS
  The 7-day H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole may elicit substantial inhibition of in vivo CYP3A activity. Although resultant elevations in plasma lansoprazole concentrations may be beneficial for H pylori eradication, caution must be exercised for possible drug interaction with a concomitantly administered CYP3A substrate (s) in patients undergoing H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole.
authors.affiliation: Department of Laboratory Medicine, Daisan Hospital, Jikei University School of Medicine, and the Department of Pharmacotherapy, Meiji Pharmaceutical University, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Ushiama
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Echizen
authors.forename: Shinobu
authors.initials: S
authors.lastname: Nachi
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ohnishi
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000658:Amoxicillin / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000097:blood* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases; D017291:Clarithromycin / Q000627:therapeutic use*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D016481:Helicobacter Infections / Q000188:drug therapy* / Q000201:enzymology* / Q000382:microbiology; D016480:Helicobacter pylori; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000378:metabolism*; D064747:Lansoprazole; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D009853:Omeprazole / Q000031:analogs & derivatives* / Q000097:blood* / Q000627:therapeutic use; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors*; D010406:Penicillins / Q000627:therapeutic use; D011500:Protein Synthesis Inhibitors / Q000627:therapeutic use*
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D000900:Anti-Bacterial Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D010406:Penicillins; D011500:Protein Synthesis Inhibitors; D064747:Lansoprazole; C001380:6 beta-hydroxycortisol; D000658:Amoxicillin; C581535:Lansoprazole Sulfone; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating; D017291:Clarithromycin; D009853:Omeprazole; D006854:Hydrocortisone