Young M A, Lettis S, Eastmond R
Department of Clinical Pharmacokinetics and Dynamics, Glaxo Wellcome Research and Development Ltd, Greenford, Middlesex, UK.
Br J Clin Pharmacol. 1998 Jan;45(1):31-5. doi: 10.1046/j.1365-2125.1998.00653.x.
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.
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.
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.
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.
曲格列酮是一种增强胰岛素作用的药物，目前正处于治疗非胰岛素依赖型糖尿病的临床开发阶段。本研究的目的是确定食物对曲格列酮全身吸收和代谢的影响。
经过一夜禁食后，12名健康男性志愿者按随机顺序分别接受以下处理：单独口服曲格列酮（400mg）；在标准化糖尿病早餐开始时同时服用曲格列酮；在标准化糖尿病早餐后30分钟服用曲格列酮，这是一项为期三个阶段的交叉研究的一部分。
当曲格列酮与食物同时服用或在进食后服用时，相对于空腹状态，血浆浓度-时间曲线下面积（AUC[末次]）的几何平均值在两种情况下均显著增加59%（95%可信区间1-150%，P=0.046；2-148%，P=0.040），分别为11.4、11.5和7.2μg·ml⁻¹·h。观察到的最大血浆浓度（Cmax）分别增加了96%和72%（95%可信区间29-197%，P=0.003；15-158%，P=0.011），分别为2.2、2.0和1.1μg·ml⁻¹。滞后时间（t(lag)）的变化无临床意义。主要循环硫酸盐代谢物的AUC(0, ∞)相对于空腹时的增加也具有显著性（分别为41%，95%可信区间5-89%，P=0.025；34%，95%可信区间1-79%，P=0.044），分别为82.6、78.6和58.5μg·h·ml⁻¹。Cmax分别增加了68%（95%可信区间10-156%，P=0.019）和65%（95%可信区间9-149%，P=0.020），分别为3.2、3.1和1.9μg·ml⁻¹。半衰期（t1/2）缩短（分别为16%和21%，95%可信区间0-30，6-33），尽管具有统计学显著性（P=0.050和P=0.009），但无临床意义，进食时、进食后和空腹时的值分别为22.3、20.4和24.5小时。在整个研究过程中，所有情况下曲格列酮的耐受性良好，餐后30分钟服用时胃肠道症状的耐受性有改善趋势。
食物可显著增强曲格列酮的吸收，对主要代谢途径影响较小。食物存在时曲格列酮吸收增加可能是胆汁中溶解度增加和溶解时间延长的结果。基于这些发现，曲格列酮应与食物同服或在进食后30分钟内服用。
