Effect of rifampicin on the pharmacokinetics of pioglitazone

Abstract

Aims: The effect of enzyme induction on the pharmacokinetics of pioglitazone, a thiazolidinedione antidiabetic drug that is metabolized primarily by CYP2C8, is not known. Rifampicin is a potent inducer of several CYP enzymes and our objective was to study its effects on the pharmacokinetics of pioglitazone in humans.

Methods: In a randomized, two-phase crossover study, ten healthy subjects ingested either 600 mg rifampicin or placebo once daily for 6 days. On the last day, they received a single oral dose of 30 mg pioglitazone. The plasma concentrations and cumulative excretion of pioglitazone and its active metabolites M-IV and M-III into urine were measured up to 48 h.

Results: Rifampicin decreased the mean total area under the plasma concentration-time curve (AUC(0-infinity)) of pioglitazone by 54% (range 20-66%; P = 0.0007; 95% confidence interval -78 to -30%) and shortened its dominant elimination half-life (t(1/2)) from 4.9 to 2.3 h (P = 0.0002). No significant effect on peak concentration (C(max)) or time to peak (t(max)) was observed. Rifampicin increased the apparent formation rate of M-IV and shortened its t(max) (P < 0.01). It also decreased the AUC(0-infinity) of M-IV (by 34%; P = 0.0055) and M-III (by 39%; P = 0.0026), shortened their t1/2 (M-IV by 50%; P = 0.0008, and M-III by 55%; P = 0.0016) and increased the AUC(0-infinity) ratios of M-IV and M-III to pioglitazone by 44% (P = 0.0011) and 32% (P = 0.0027), respectively. Rifampicin increased the M-IV/pioglitazone and M-III/pioglitazone ratios in urine by 98% (P = 0.0015) and 95% (P = 0.0024). A previously unrecognized metabolite M-XI, tentatively identified as a dihydroxy metabolite, was detected in urine during both phases, and rifampicin increased the ratio of M-XI to pioglitazone by 240% (P = 0.0020).

Conclusions: Rifampicin caused a substantial decrease in the plasma concentration of pioglitazone, probably by induction of CYP2C8. Concomitant use of rifampicin with pioglitazone may decrease the efficacy of the latter drug.

Figures

Figure 1

The metabolism of pioglitazone in humans [2]. M-XI is a previously unrecognized metabolite

Figure 2

Mean ± SEM plasma concentration-time curves for pioglitazone in ten healthy subjects after a single oral dose of 30 mg pioglitazone on the last day of a 6-day treatment with placebo (○) or 600 mg rifampicin (•) once daily. The inset depicts the same data on a semilogarithmic scale

Figure 3

Mean ±SEM plasma concentration-time curves for metabolites M-IV and M-III in ten healthy volunteers after a single oral dose of 30 mg pioglitazone on the last day of a 6-day treatment with placebo (○) or 600 mg rifampicin (•) once daily

Figure 4

Mean ±SEM AUC ratios and Ae ratios for pioglitazone and its metabolites in 10 healthy subjects after a single oral dose of 30 mg pioglitazone on the last day of a 6-day treatment with placebo (Pl) or 600 mg rifampicin (Rif) given once daily

Figure 5

Mean ±SEM amounts of pioglitazone, M-IV, M-III, M-V and M-XI excreted in urine within 48 h [Ae(0–48)] in 10 healthy subjects after a single oral dose of 30 mg pioglitazone on the last day of a 6-day treatment with 600 mg rifampicin (•) or placebo (○) once daily