Pharmacokinetic variables of the pioglitazone main primary metabolite M-IV after a single oral dose of 15 mg of pioglitazone on day 3 of a 6-day treatment with placebo or 160 mg of trimethoprim twice daily in subjects with the CYP2C8*1/*1 genotype (n = 8), CYP2C8*1/*3 genotype (n = 5), and CYP2C8*3/*3 genotype (n = 3)
Variable for M-IV | Placebo Phase (Control)a | Trimethoprim Phasea | Trimethoprim Phase, % of Controlb | p between Phasesc | p between Genotypesc |
---|---|---|---|---|---|
kf (h–1) | |||||
*1/*1 | 0.12 ± 0.043 | 0.091 ± 0.039 | 74 (40–124) | ||
*1/*3 | 0.23 ± 0.086** | 0.12 ± 0.045 | 51 (35–71) | ||
*3/*3 | 0.18 ± 0.056 | 0.11 ± 0.042 | 62 (37–100) | ||
Mean | 0.17 ± 0.075 | 0.10 ± 0.040 | 61 (35–124) | <0.001 | 0.057 |
Cmax (ng/ml) | |||||
*1/*1 | 271 ± 62.6 | 253 ± 38.4 | 94 (62–135) | ||
*1/*3 | 299 ± 54.9 | 300 ± 47.0 | 100 (83–160) | ||
*3/*3 | 269 ± 118 | 313 ± 112 | 116 (82–189) | ||
Mean | 279 ± 68.3 | 279 ± 60.5 | 100 (62–189) | 0.600 | 0.448 |
t1/2 (h) | |||||
*1/*1 | 21.2 ± 3.5 | 22.5 ± 4.0 | 106 (95–134) | ||
*1/*3 | 18.8 ± 2.8 | 19.7 ± 3.9 | 105 (86–129) | ||
*3/*3 | 23.4 ± 6.5 | 21.8 ± 1.8 | 93 (78–118) | ||
Mean | 20.9 ± 4.0 | 21.5 ± 3.7 | 103 (78–134) | 0.804 | 0.343 |
AUC0–∞ (mg · h/l) | |||||
*1/*1 | 11.6 ± 3.08 | 12.2 ± 3.48 | 105 (75–126) | ||
*1/*3 | 11.2 ± 1.86 | 12.6 ± 2.62 | 113 (99–142) | ||
*3/*3 | 12.3 ± 4.72 | 14.6 ± 5.26 | 119 (96–156) | ||
Mean | 11.6 ± 2.91 | 12.8 ± 3.47 | 110 (75–156) | 0.048 | 0.829 |
M-IV/pioglitazone AUC0–∞ ratio | |||||
*1/*1 | 2.31 ± 0.41 | 1.79 ± 0.16 | 77 (64–92) | ||
*1/*3 | 2.99 ± 0.48* | 2.16 ± 0.25** | 72 (62–98) | ||
*3/*3 | 3.36 ± 0.73** | 2.79 ± 0.27***† | 83 (77–99) | ||
Mean | 2.72 ± 0.64 | 2.09 ± 0.43 | 77 (62–99) | <0.001 | 0.001 |
kf, apparent formation rate constant; Cmax, peak plasma concentration; t1/2, elimination half-life; AUC0–∞, area under the plasma concentration-time curve from time 0 to infinity
↵ a Values are mean ± S.D.
↵ b Values are mean (range)
↵ c p value from repeated-measures ANOVA with genotype as between-subjects factor
↵* p < 0.05 versus *1/*1
↵** p < 0.01 versus *1/*1
↵*** p < 0.001 versus *1/*1
↵† p < 0.01 versus *1/*3