Hermann R, Wildgrube H J, Ruus P, Niebch G, Nowak H, Gleiter C H
Department of Clinical Pharmacology, Medical Research, ASTA Medica AG, 60314 Frankfurt/Main, Weismüllerstr. 45, Germany.
Eur J Pharm Sci. 1998 Jan;6(1):27-37. doi: 10.1016/s0928-0987(97)00065-1.
The objective of this study was to determine the impact of prolonged gastric emptying in patients with insulin dependent diabetes mellitus (IDDM) on the bioavailability of the R(+)- and S(-)-thioctic acid (TA) enantiomers. Gastric emptying time (GET) was assessed in 30 healthy volunteers and 22 patients with IDDM using sequential ultrasonography after a standardized solid-liquid test meal. Pharmacokinetics and absolute bioavailability (F) of the TA-enantiomers were studied using a randomized, open two-way crossover design with administrations of oral and intravenous single doses of 200 mg rac-TA. GET in healthy subjects was 134.7+/-21.6 min, the normal range was calculated from 88.3 to 181.1 min. The mean GET in all IDDM patients was significantly prolonged (178.2+/-28.1 min; P<0.001). Only 50% of the patients (n=11) were found to have normal GET (group A), the other half of the population (n=11) were considered to have delayed GET (group B). Mean GET values were 156.9+/-21.5 in group A (P=0.028) and 199.4+/-13.9 min in group B, respectively, suggesting that gastric motility is significantly different from non-diabetic controls even in patients with apparently normal gastric emptying. Times to peak plasma concentrations (t(max)) of both TA-enantiomers were similar in both groups and thus, unrelated to measures of gastric emptying. In contrast, maximum concentrations (C(max)) and area-under-the-curve values (AUC) of both enantiomers were reduced by about 30% in patients with delayed GET. Although these differences resulted in statistical significance for the AUC of both enantiomers (P<0.05), linear regression analysis showed only modest correlation between GET and the extent of TA-enantiomer absorption (r2=0.31 and 0.22 for R(+)-/S(-)-TA, respectively). The study suggests that prolonged gastric emptying is frequently present in IDDM. Delayed gastric emptying, however, does not substantially affect the rate and extent of absorption of both TA-enantiomers.
本研究的目的是确定胰岛素依赖型糖尿病（IDDM）患者胃排空时间延长对R(+)-和S(-)-硫辛酸（TA）对映体生物利用度的影响。在30名健康志愿者和22名IDDM患者中，采用标准化的固体-液体试验餐后序贯超声检查评估胃排空时间（GET）。使用随机、开放的双向交叉设计，口服和静脉注射单剂量200mg消旋TA，研究TA对映体的药代动力学和绝对生物利用度（F）。健康受试者的GET为134.7±21.6分钟，正常范围为88.3至181.1分钟。所有IDDM患者的平均GET显著延长（178.2±28.1分钟；P<0.001）。仅50%的患者（n=11）GET正常（A组），另一半患者（n=11）被认为GET延迟（B组）。A组的平均GET值为156.9±21.5（P=0.028），B组为199.4±13.9分钟，这表明即使在胃排空明显正常的患者中，胃动力与非糖尿病对照组也存在显著差异。两组中两种TA对映体的血浆浓度达峰时间（t(max)）相似，因此与胃排空指标无关。相比之下，GET延迟的患者中两种对映体的最大浓度（C(max)）和曲线下面积值（AUC）降低了约30%。虽然这些差异导致两种对映体的AUC具有统计学意义（P<0.05），但线性回归分析显示GET与TA对映体吸收程度之间仅存在适度相关性（R(+)-/S(-)-TA的r2分别为0.31和0.22）。该研究表明，IDDM患者中经常存在胃排空时间延长的情况。然而，胃排空延迟并未实质性影响两种TA对映体的吸收速率和程度。
