Zimmermann T, Wehling M, Schulz H U
G. Pohl-Boskamp GmbH & Co., Hohenlockstedt.
Arzneimittelforschung. 1998 Jan;48(1):5-12.
Two open, randomized cross-over trials were performed in 18 healthy volunteers each to evaluate the relative bioavailability and the pharmacokinetics of chloral hydrate (CAS 302-17-0), the active ingredient of Chloraldurat 500 (immediate release capsules, CH), Chloraldurat rot (immediate release capsules, CR) and Chloraldurat blau (enteric-coated modified release capsules, CB). In the first study the male subjects, aged 21 to 31 years, were randomly given one capsule of CH or 500 mg of chloral hydrate as drinking solution. In the second study the volunteers, aged 20 to 28 years, received either one capsule of CR or one capsule of CB or 250 mg of chloral hydrate as drinking solution. The time of administration was between 6:30 and 7:30 a.m. and the capsules had to be swallowed with 150 ml water. The reference medication consisted of 150 ml drinking solution. The wash out time in both studies was 4 weeks. Prior to the administration and (2, 4, 6, only for CH) 8, 10, 15, 20, 40, 60 min and 1.5, 2, 4, 6, 8, 12, 24, 36, 48, 72, 96, 144, 192, 240 (and 408 only for CR/CB) h afterwards blood samples of 4.5 ml were taken from the antecubital vein. Additional 4.5 ml were drawn before and 10, 20, 40 and 60 min after administration to detect unchanged chloral hydrate. In the second study times of blood sampling were modified up to 4 h after administration due to the estimated later onset of release from CB in comparison to CR. Blood samples were centrifuged within 20 min, the plasma was separated and immediately frozen at -20 degrees C. Due to the extremely short terminal half-life of chloral hydrate its active metabolite trichloroethanol is regarded as the pharmacokinetically relevant parameter for the assessment of the bioavailability of the parent substance. Compared to the reference formulation (drinking solution) the bioavailability of trichloroethanol was 94.8% (CH), 100.7% (CR) and 101.6 (CB), respectively. The maximum plasma concentrations (Cmax) of trichloroethanol were 5176 ng/ml after intake of CH (reference 6131 ng/ml), after intake of CR 3241 ng/ml and CB 3279 ng/ml (reference 2993 ng/ml). Maximum plasma concentrations (tmax) of trichloroethanol were reached after 0.67 h (reference) and after 0.98 (CH), 0.76 (CR) and 2.38 h (CB), respectively. The terminal half-life for trichloroethanol was calculated to be 9.3 to 10.2 h, for the inactive metabolite trichloracetic acid the half-life ranged from 89 to 94 h. Chloral hydrate itself could be detected only 8 to 60 min after application at very low concentrations in some of the plasma samples. It is justified to characterize its bioavailability by the active metabolite trichloroethanol due to the extremely short terminal half-life and high variability of the parent substance.
两项开放、随机交叉试验分别在18名健康志愿者身上进行，以评估水合氯醛（CAS 302-17-0）的相对生物利用度和药代动力学。水合氯醛是Chloraldurat 500（速释胶囊，CH）、Chloraldurat rot（速释胶囊，CR）和Chloraldurat blau（肠溶包衣缓释胶囊，CB）的活性成分。在第一项研究中，年龄在21至31岁的男性受试者被随机给予一粒CH胶囊或500毫克水合氯醛作为饮用溶液。在第二项研究中，年龄在20至28岁的志愿者接受一粒CR胶囊、一粒CB胶囊或250毫克水合氯醛作为饮用溶液。给药时间为上午6:30至7:30，胶囊必须用150毫升水吞服。参比制剂为150毫升饮用溶液。两项研究的洗脱期均为4周。给药前以及（仅CH组在）给药后2、4、6、8、10、15、20、40、60分钟以及1.5、2、4、6、8、12、24、36、48、72、96、144、192、240小时（CR/CB组仅在408小时）从肘前静脉采集4.5毫升血样。给药前以及给药后10、20、40和60分钟额外采集4.5毫升血样以检测未变化的水合氯醛。在第二项研究中，由于预计CB的释放比CR晚，给药后4小时内的采血时间进行了调整。血样在20分钟内离心，分离出血浆并立即在-20℃冷冻。由于水合氯醛的终末半衰期极短，其活性代谢物三氯乙醇被视为评估母体物质生物利用度的药代动力学相关参数。与参比制剂（饮用溶液）相比，三氯乙醇的生物利用度分别为94.8%（CH）、100.7%（CR）和101.6%（CB）。服用CH后三氯乙醇的最大血浆浓度（Cmax）为5176纳克/毫升（参比为6131纳克/毫升），服用CR后为3241纳克/毫升，服用CB后为3279纳克/毫升（参比为2993纳克/毫升）。三氯乙醇的最大血浆浓度达峰时间（tmax）分别在0.67小时（参比）以及0.98小时（CH）、0.76小时（CR）和2.38小时（CB）后。三氯乙醇的终末半衰期计算为9.3至10.2小时，非活性代谢物三氯乙酸的半衰期为89至94小时。仅在部分血浆样本中，给药后8至60分钟可检测到极低浓度的水合氯醛本身。由于母体物质终末半衰期极短且变异性高，用活性代谢物三氯乙醇来表征其生物利用度是合理的。
