Effect of rifampicin on the pharmacokinetics and pharmacodynamics of nateglinide in healthy subjects

Abstract

Aims: 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.

Figure 1

Mean (± SEM) plasma concentrations of nateglinide (a) and its M7 metabolite (b) in 10 healthy volunteers following a single oral dose of 60 mg nateglinide after 5 days treatment with placebo (○) or 600 mg rifampicin (•) once daily. Insets depict the same data on a semilogarithmic scale.

Figure 2

Individual C_max (a) and AUC(0,7 h) (b) values of nateglinide in 10 healthy volunteers following a single oral dose of 60 mg nateglinide after 5 days treatment with placebo or 600 mg rifampicin once daily.

Figure 3

Mean (± SEM) change in blood glucose concentrations in 10 healthy volunteers following a single oral dose of 60 mg nateglinide after 5 days treatment with placebo (○) or 600 mg rifampicin (•) once daily.