[The relative bioavailability and pharmacokinetics of chloral hydrate and its metabolites]

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.