TABLE 3

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