Improvement in the gastrointestinal absorption of troglitazone when taken with, or shortly after, food.
OBJECTIVE
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.
Young
M A
MA
Department of Clinical Pharmacokinetics and Dynamics, Glaxo Wellcome Research and Development Ltd, Greenford, Middlesex, UK.
Lettis
S
S
Eastmond
R
R
D000328:Adult; D002839:Chromans / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004064:Digestive System / Q000378:metabolism*; D004435:Eating / Q000502:physiology*; D005502:Food; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D008297:Male; D013844:Thiazoles / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D045162:Thiazolidinediones; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077288:Troglitazone