Improvement in the gastrointestinal absorption of troglitazone when taken with, or shortly after, food

Br J Clin Pharmacol. 1998 Jan;45(1):31-5. doi: 10.1046/j.1365-2125.1998.00653.x.

Abstract

Aims: Troglitazone, an insulin action enhancing agent, is currently in clinical development for the treatment of non insulin dependent diabetes mellitus. The objective of this study was to establish the effect of food on the systemic absorption and metabolism of troglitazone.

Methods: After an overnight fast, 12 healthy male volunteers each received, in random order, troglitazone (400 mg orally) alone, concomitantly with (at the start of), and 30 min after, a standardized diabetic breakfast as part of a three-period crossover study.

Results: When troglitazone was administered with or after food, geometric mean values of area under the plasma concentration-time curves (AUC[last]) relative to fasting state were increased significantly by 59% in both cases (95% CI 1-150%, P=0.046 and 2-148%, P=0.040) with values of 11.4, 11.5 and 7.2 microg ml(-1) h respectively. Maximum observed plasma concentration (Cmax) increased by 96% and 72% (95% CI 29-197%, P=0.003 and 15-158%, P=0.011) with values of 2.2, 2.0 and 1.1 microg ml(-1) respectively. Changes in t(lag) were not clinically significant. Increases in AUC(0, infinity) for the main circulating sulphate metabolite relative to fasting were also significant (41%, 95% CI 5-89%, P=0.025 and 34%, 95% CI 1-79%, P= 0.044 respectively) with values of 82.6, 78.6 and 58.5 microg h ml(-1). Cmax increased by 68% (95%, CI 10-156%, P=0.019) and 65% (95% CI 9-149%, P=0.020) with values of 3.2, 3.1 and 1.9 microg ml(-1) respectively. Reductions in t1/2 (16 and 21%, 95% CI 0-30, 6-33) although statistically significant (P=0.050 and P=0.009) were not clinically significant with values of 22.3, 20.4 and 24.5 h for with food, after food and fasting respectively. Troglitazone was well tolerated in all cases throughout the study with a trend for improved tolerability of gastrointestinal symptoms when taken 30 min after a meal.

Conclusions: The absorption of troglitazone is enhanced significantly by food with little effect on the main metabolic pathway. Increased absorption of troglitazone in the presence of food is likely to be a consequence of enhanced solubility in bile combined with an increase in dissolution time. On the basis of these findings, troglitazone should be taken either with, or up to 30 min after, food.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Chromans / adverse effects
  • Chromans / metabolism
  • Chromans / pharmacokinetics*
  • Cross-Over Studies
  • Digestive System / metabolism*
  • Eating / physiology*
  • Food
  • Humans
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacokinetics*
  • Intestinal Absorption
  • Male
  • Thiazoles / adverse effects
  • Thiazoles / metabolism
  • Thiazoles / pharmacokinetics*
  • Thiazolidinediones*
  • Troglitazone

Substances

  • Chromans
  • Hypoglycemic Agents
  • Thiazoles
  • Thiazolidinediones
  • Troglitazone