Authors: Jaakkola, Tiina; Backman, Janne T.; Neuvonen, Mikko; Laitila, Jouko; Neuvonen, Pertti J.

Source: British Journal of Clinical Pharmacology, Volume 61, Number 1, January 2006 , pp. 70-78(9)

Publisher: Wiley-Blackwell

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−∞) 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−∞ 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−∞ 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.

Keywords: pioglitazone; rifampicin; drug interaction; CYP2C8; pharmacokinetics; metabolism

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2125.2005.02515.x

Affiliations: 1: Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland

Publication date: 2006-01-01

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