Pharmacokinetics of Clomethiazole in Healthy Adults

Abstract

The systemic availability of clomethiazole was assessed by comparing blood levels after intravenous and oral administration. Clomethiazole was rapidly absorbed after oral administration to volunteers, particularly when administered as syrup. The fraction of the given dose that reached the systemic circulation after 1 capsule of clomethiazole (192 mg clomethiazole) was 0.25±0.18, after 2 capsules (384 mg clomethiazole) 0.38±0.18, and after 15 ml syrup (480 mg clomethiazole) 0.42±0.20. The time‐blood concentration profiles were consistent with a two‐compartment open model and the mean elimination half‐lives of 3.6‐5.0 hrs. were found for the different formulations and administration routes. Elimination half‐lives showed little variation and a mean systemic clearance of 49 ml/min./kg was found for clomethiazole after intravenous administration. Clomethiazole is bound to human plasma proteins (63.4±1.6%, 37°), a binding which is not affected by Vacutainer® sample tubes. The blood/plasma distribution of clomethiazole was 0.76±0.02 at 37°. A sensitive mass fragmentographic assay for the determination of clomethiazole in blood/plasma down to levels of 1 ng/ml (6.2 nmol/l) is described.

Linking in Vitro Lipolysis and Microsomal Metabolism for the Quantitative Prediction of Oral Bioavailability of BCS II Drugs Administered in Lipidic Formulations

“…The LFs of testosterone undecanoate (Andriol and Restandol) were discarded as well because the stability of this ester prodrug in the gastrointestinal tract remains unknown. Eventually, five medicines were short-listed: Marinol (THC), 26,27,54−58 One-Alpha capsules (alfacalcidol), 59,60 Rocaltrol (calcitriol), 60,61 Heminevrin (clomethiazole edisilate), 62,63 and Neoral (CsA). 28−30,64−69 Marinol (sesame oil), One-Alpha capsules (sesame oil and α-tocopherol), Rocaltrol (fractionated triglycerides of coconut oil or palm oil) and Heminevrin (fractionated coconut oil) are all Type I lipidic formulations, whereas Neoral is a SEDDS consisting of lipids, surfactants and cosolvents (Type IIIA).…”

“…Eventually, five medicines were short-listed: Marinol (THC), ,,− One-Alpha capsules (alfacalcidol), , Rocaltrol (calcitriol), , Heminevrin (clomethiazole edisilate), , and Neoral (CsA). − ,− Marinol (sesame oil), One-Alpha capsules (sesame oil and α-tocopherol), Rocaltrol (fractionated triglycerides of coconut oil or palm oil) and Heminevrin (fractionated coconut oil) are all Type I lipidic formulations, whereas Neoral is a SEDDS consisting of lipids, surfactants and cosolvents (Type IIIA). For the sake of formulation diversity, we decided to select one Type I formulation (Marinol, already available in our laboratory), and one Type III (Neoral).…”

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders

“…The withdrawal syndrome is characterized by the emergence of symptoms not previously experienced, such as agitation, headache, dizziness, dysphoria, irritability, fatigue, depersonalization, hypersensitivity to noise and visual stimuli. Physical symptoms which have been described include nausea, vomiting, muscle cramps, sweating, Gefvert et al, 1998;j Davis et al, 1999;k Markantonis et al, 2008;l DeMuro et al, 2000;m Rizzo et al, 2002;n Di et al, 1998;o Zimmermann et al, 1998;p Merdink et al, 2008;q Sellers et al, 1978;r Rätz et al, 1999;s Jostell et al, 1978;t Koytchev et al, 1994;u Strenkoski-Nix et al, 2000;w Abanades et al, 2006;y http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000593/WC500057103.pdf NK: not known.…”

Comparison of Clomethiazole and Diazepam in the Treatment of Alcohol Withdrawal Syndrome in Clinical Practice

“…It acts through a potentiating effect on the GABA-A receptor complex [26,27,28]. Its elimination half-life lies between 4 and 6 h [25,29] and it is also eliminated by hepatic metabolism [30]. An increase in respiratory secretion is the most common, usually mild adverse event [31].…”

“…Clomethiazole, a sedative, tranquilizing, and anticonvulsant drug [25,] is mainly used in Europe [9]. It acts through a potentiating effect on the GABA-A receptor complex [26,27,28].…”