FIGURES AND TABLES

Figure 1.

Metabolic scheme of pioglitazone (according to Eckland and Danhof²).

Figure 2.

Mean (SEM) plasma concentrations of pioglitazone in 12 healthy volunteers after single oral dose of 15 mg pioglitazone on day 3 of 4-day treatment with 600 mg gemfibrozil (solid squares), 100 mg itraconazole (first dose, 200 mg) (solid triangles), both gemfibrozil and itraconazole (open diamonds), or placebo (open circles) twice daily. Inset depicts the same data on a semilogarithmic scale.

Figure 3.

Mean (SEM) plasma concentrations of metabolites M-III and M-IV in 12 healthy volunteers after single oral dose of 15 mg pioglitazone on day 3 of 4-day treatment with 600 mg gemfibrozil (solid squares), 100 mg itraconazole (first dose, 200 mg) (solid triangles), both gemfibrozil and itraconazole (open diamonds), or placebo (open circles) twice daily.

Figure 4.

Mean (SEM) AUC(0–48) (area under plasma concentration-time curve from time 0 to 48 hours) ratios and Ae(0–48) (amount excreted in urine within 48 hours) ratios of pioglitazone and metabolites M-III, M-IV, and M-V in 12 healthy volunteers after single oral dose of 15 mg pioglitazone on day 3 of 4-day treatment with placebo (P), 100 mg itraconazole (first dose, 200 mg) (I), 600 mg gemfibrozil (G), or both gemfibrozil and itraconazole (G-I) twice daily. Bonferroni-adjusted P values were as follows: asterisk, P < .001, versus placebo phase; dagger, P < .001, versus itraconazole phase; double dagger, P < .05, versus placebo phase; section symbol, P < .05, versus itraconazole phase.

Figure 5.

Mean (SEM) amounts of pioglitazone, M-III, M-IV, and M-V excreted in urine within 48 hours (Ae) in 12 healthy volunteers after single oral dose of 15 mg pioglitazone on day 3 of 4-day treatment with 600 mg gemfibrozil (solid squares), 100 mg itraconazole (first dose, 200 mg) (solid triangles), both gemfibrozil and itraconazole (open diamonds), or placebo (open circles) twice daily. Bonferroni-adjusted P values were as follows: asterisk, P < .001, versus placebo phase; section symbol, P < .05, versus itraconazole phase; double dagger, P < .05, versus placebo and itraconazole phases; asterisk with double dagger, P < .001, versus placebo and itraconazole phases.

Figure 6.

Mean (SEM) plasma concentrations of itraconazole, hydroxyitraconazole, and gemfibrozil in 12 healthy volunteers on days 3 to 5 of 4-day treatment with 100 mg itraconazole (first dose, 200 mg) (solid triangles), 600 mg gemfibrozil (solid squares), or both gemfibrozil and itraconazole (open diamonds) twice daily. Time 0 refers to administration of gemfibrozil and itraconazole (ie, 1 hour before the administration of pioglitazone). Additional doses of either gemfibrozil or itraconazole or both gemfibrozil and itraconazole were given 12, 24, and 36 hours after pioglitazone intake.

Table I - Pharmacokinetic variables of pioglitazone in 12 healthy volunteers after a single oral dose of 15 mg pioglitazone on day 3 of a 4-day treatment with 600 mg gemfibrozil, 100 mg itraconazole (first dose, 200 mg), both gemfibrozil and itraconazole, or placebo twice daily.