Effect of rifampicin on the pharmacokinetics of pioglitazone.
OBJECTIVE
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.
Jaakkola
Tiina
T
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Backman
Janne T
JT
Neuvonen
Mikko
M
Laitila
Jouko
J
Neuvonen
Pertti J
PJ
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D000077205:Pioglitazone; D012293:Rifampin / Q000008:administration & dosage*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; C510846:M-II compound; C510847:M-IV compound; D045162:Thiazolidinediones; D012293:Rifampin; D000077205:Pioglitazone