Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects.
OBJECTIVE
Our aim was to investigate the effects of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide, a novel short-acting antidiabetic drug.


METHODS
In a randomized crossover study with two phases, 10 healthy volunteers took 600 mg rifampicin or placebo orally once daily for 5 days. On day 6 of both phases, they ingested a single 60 mg dose of nateglinide. Plasma nateglinide and blood glucose concentrations were measured for up to 7 h postdose.


RESULTS
Rifampicin decreased the mean AUC(0,7 h) of nateglinide by 24% (range 5-53%; P = 0.0009) and shortened its half-life (t(1/2)) from 1.6 to 1.3 h (P = 0.001). However, the peak plasma nateglinide concentration (Cmax) remained unchanged. The AUC(0,7 h) of the M7 metabolite of nateglinide was decreased by 19% (P = 0.002) and its t(1/2) was shortened from 2.1 to 1.6 h by rifampicin (P = 0.008). Rifampicin had no significant effect on the blood glucose-lowering effect of nateglinide.


CONCLUSIONS
Rifampicin modestly decreased the plasma concentrations of nateglinide probably by inducing its oxidative biotransformation. In some patients, rifampicin may reduce the blood glucose-lowering effect of nateglinide.
Niemi
Mikko
M
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. mikko.niemi@helsinki.fi
Backman
Janne T
JT
Neuvonen
Mikko
M
Neuvonen
Pertti J
PJ
D000328:Adult; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D018592:Cross-Over Studies; D003510:Cyclohexanes / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology*
D000904:Antibiotics, Antitubercular; D001786:Blood Glucose; D003510:Cyclohexanes; D007004:Hypoglycemic Agents; D000077715:Nateglinide; D010649:Phenylalanine; D012293:Rifampin