Pharmacokinetics and pharmacodynamics of clomethiazole after oral and rectal administration in healthy subjects

Clomethiazole, a sedative-hypnotic and anticonvulsant drug, has been succes sfully administered orally and intravenously, but in cases where either of these methods presents complications, rectal administration may represent a practical alternative. We sought to compare the single-dose pharmacokineti cs and pharmacodynamics of clomethiazole after oral and rectal administrati on. Ten healthy adult volunteers were given 600 mg clomethiazole edisylate (corresponding to 390 mg clomethiazole base) in 2 capsules as a single oral or rectal dose in a double-masked, double-dummy, crossover fashion. Serum concentrations were measured up to 10 hours after administration using a sp ecific highperformance liquid chromatography method. Computerized reaction- time measurement and visual analogue scales (VAS) were used to assess drug effects. Peak serum concentrations were significantly higher after oral adm inistration (mean +/- SEM, oral 1.76 +/- 0.47 mu g/mL vs rectal 0.48 +/- 0. 14 mu g/mL; P = 0.03) and appeared earlier (55 +/- 12 vs 89 +/- 11 min; P = 0.04). Area under the concentration-time curve values were similar after a dministration by both routes (oral 116 +/- 20.6 vs rectal 105 +/- 36.0 mu g .min/mL), with a relative rectal bioavailability of 90% compared with oral administration. The objective pharmacodynamic effects on reaction time (inc rease of 104 +/- 26 vs 66 +/- 22 ms, oral vs rectal) and working speed (dec rease of 132 +/- 38 vs 97 +/- 32 ms, oral vs rectal) were not significantly different. Subjective pharmacodynamic effects, as measured on the VAS, wer e comparable with both routes of administration. Clomethiazole was well tol erated, with a similar adverse effect profile for both routes of administra tion. The effects of rectal dosing of clomethiazole were similar to those o f oral dosing but appeared to occur later. Our results suggest that rectal administration of a single 600-mg clomethiazole edisylate dose bears no saf ety risk. Therefore, rectal administration could be considered when neither oral nor parenteral administration is possible and a later onset of effect is not critical.