The cytochrome P4503A4 inhibitor clarithromycin increases the plasma concentrations and effects of repaglinide.
OBJECTIVE
Our objective was to study the effects of the macrolide antibiotic clarithromycin on the pharmacokinetics and pharmacodynamics of repaglinide, a novel short-acting antidiabetic drug.


METHODS
In a randomized, double-blind, 2-phase crossover study, 9 healthy volunteers were treated for 4 days with 250 mg oral clarithromycin or placebo twice daily. On day 5 they received a single dose of 250 mg clarithromycin or placebo, and 1 hour later a single dose of 0.25 mg repaglinide was given orally. Plasma repaglinide, serum insulin, and blood glucose concentrations were measured up to 7 hours.


RESULTS
Clarithromycin increased the mean total area under the concentration-time curve of repaglinide by 40% (P <.0001) and the peak plasma concentration by 67% (P <.005) compared with placebo. The mean elimination half-life of repaglinide was prolonged from 1.4 to 1.7 hours (P <.05) by clarithromycin. Clarithromycin increased the mean incremental area under the concentration-time curve from 0 to 3 hours of serum insulin by 51% (P <.05) and the maximum increase in the serum insulin concentration by 61% (P <.01) compared with placebo. No statistically significant differences were found in the blood glucose concentrations between the placebo and clarithromycin phases.


CONCLUSIONS
Even low doses of the cytochrome P4503A4 (CYP3A4) inhibitor clarithromycin increase the plasma concentrations and effects of repaglinide. Concomitant use of clarithromycin or other potent inhibitors of CYP3A4 with repaglinide may enhance its blood glucose-lowering effect and increase the risk of hypoglycemia.
Niemi
M
M
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Neuvonen
P J
PJ
Kivistö
K T
KT
D000328:Adult; D000704:Analysis of Variance; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017291:Clarithromycin / Q000008:administration & dosage / Q000494:pharmacology*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values; D013997:Time Factors
D000900:Anti-Bacterial Agents; D001786:Blood Glucose; D002219:Carbamates; D065607:Cytochrome P-450 Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D010880:Piperidines; C072379:repaglinide; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017291:Clarithromycin