Article date: January 2006
By: Tiina Jaakkola, Janne T. Backman, Mikko Neuvonen, Jouko Laitila, Pertti J. Neuvonen, in Volume 61, Issue 1, pages 70-78
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 (AUC0−∞) of pioglitazone by 54% (range 20–66%; P = 0.0007; 95% confidence interval −78 to −30%) and shortened its dominant elimination half‐life (t1/2) from 4.9 to 2.3 h (P = 0.0002). No significant effect on peak concentration (Cmax) or time to peak (tmax) was observed. Rifampicin increased the apparent formation rate of M‐IV and shortened its tmax (P < 0.01). It also decreased the AUC0−∞ 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 AUC0−∞ 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.
DOI: 10.1111/j.1365-2125.2005.02515.x
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