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Effect of rifampicin on the pharmacokinetics of pioglitazone
Author(s) -
Jaakkola Tiina,
Backman Janne T.,
Neuvonen Mikko,
Laitila Jouko,
Neuvonen Pertti J.
Publication year - 2006
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02515.x
Subject(s) - pioglitazone , pharmacokinetics , rifampicin , pharmacology , crossover study , thiazolidinedione , chemistry , medicine , elimination rate constant , placebo , endocrinology , type 2 diabetes , antibiotics , diabetes mellitus , volume of distribution , biochemistry , alternative medicine , pathology
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 t 1/2 (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.