Relative bioavailability of 3 different chlormezanone 200 mg preparations after single dose oral administration.

Eighteen male volunteers have been treated with 3 different oral formulations of chlormezanone according to a randomized 3-way change-over design. The test preparation was a tablet (Krewel), reference preparation 1 was a suspension (Krewel), and reference preparation 2 was a tablet (Muskel Trancopal, Sanofi Winthrop GmbH). All preparations contained 200 mg of chlormezanone. Divided in 3 periods the volunteers received single doses of the test and the 2 reference formulations, respectively. Blood samples have been drawn immediately prior to each administration and at 21 sampling points within 144 h after dosing. A wash-out period of 2 weeks was maintained between successive drug doses. Plasma concentrations of chlormezanone were determined by a validated reversed-phase HPLC method with UV detection, with a lower limit of quantification of 0.1 microgram/ml. The following mean values have been obtained for the test preparation: AUC0-infinity 121 micrograms x h/ml, Cmax of 2.9 micrograms/ml at 1.5 h, t1/2 38 h, after administration of the suspension: AUC0-infinity 111 micrograms x h/ml, Cmax 2.6 micrograms/ml, tmax 1.5 h, t1/2 40 h, and after administration of the reference tablet: AUC0-infinity 121 micrograms x h/ml, Cmax 3.0 micrograms/ml, tmax 1.6 h, t1/2 38 h. The test preparation shows a relative bioavailability of 109% compared to the suspension and has been proven to be bioequivalent to the reference tablet with regard to extent and rate of absorption.

Pharmacokinetics of chlormezanone in elderly patients.

The pharmacokinetics of Chlormezanone (CM) has been determined after a single oral dose of 400 mg CM in 5 young volunteers (28 y) and in 8 elderly patients (79 y). In the young subjects, CM was rapidly absorbed and distributed, and was slowly eliminated with a half-life of 38 h major metabolites were not detected in plasma or urine. Only 3% of CM was excreted unchanged in urine. In elderly patients absorption was delayed but not reduced; the Cmax and AUC did not differ from those in younger subjects, the elimination rate was reduced compared to the younger subjects (mean 54 h). The increase was in part related to the reduction in renal function and metabolism observed in aging. However, the change in pharmacokinetics was moderate and no adjustment in dosage seems necessary for treatments of limited duration in elderly patients.

Chlormezanone plasma and blood levels in patients after single and repeated oral doses and after suicidal drug overdose.

Chlormezanone plasma concentrations were determined in 5 volunteers (group 1) after a single oral dose of 200 mg of chlormezanone with high performance liquid chromatography. A plasma elimination half-life of 23 +/- 2.3 h was calculated. The mean peak chlormezanone plasma level was 1.86 +/- 0.2 micrograms/ml, 1 h after ingestion. Additionally, chlormezanone plasma levels were determined after repeated oral doses of chlormezanone recommended for treatment of muscular spasms due to degenerative skeletal disease. After 5 days of repeated daily doses of 3 x 200 mg (group 2; 12 patients) or 3 x 400 mg (group 3; 10 patients) of chlormezanone, mean predose chlormezanone plasma levels were 12.0 +/- 2.0 micrograms/ml (group 2) and 22.7 +/- 4.0 micrograms/ml (group 3), respectively. Comparable plasma concentrations were determined after 10 days of repeated doses of 3 x 200 mg or 3 x 400 mg of chlormezanone in 3 patients from each of these 2 groups. In 7 patients of group 3, chlormezanone had to be discontinued on the 5th day due to increasing muscular weakness, ataxia and exercise-inducible tachycardia. After a loading dose of 800 mg and repeated doses of 3 x 200 mg chlormezanone to 5 patients (group 4), plasma levels of 6.5 +/- 2.1 micrograms/ml, 8.9 +/- 2.2 micrograms/ml, 12.7 +/- 2.0 micrograms/ml, and 10.4 +/- 2.4 micrograms/ml were determined after 2, 8, 16, and 36 h, respectively. Trace amounts of a degradation product of the acid-labile chlormezanone could be detected in plasma besides the unchanged drug after administration of repeated oral doses.(ABSTRACT TRUNCATED AT 250 WORDS)

[Pharmacokinetics of chlormezanone in healthy volunteers]. / Pharmacocinétique de la chlormézanone chez le volontaire sain.

The kinetics of chlormezanone were determined after oral administration of single (400 mg) and multiple doses (400 mg/day during 8 days) in eight young healthy male subjects. Plasma levels determination had been carried out by HPLC. After single dose administration, Cmax concentrations 4.62 +/- 0.75 mg/l were obtained (Tmax) 2.18 +/- 1.49 h after drug intake. Area under plasma concentrations time curve was 224.93 +/- 27.79 mg.h/l and terminal half-life 40.50 +/- 4.19 h. On chronic regimen, chlormezanone accumulates in the body: trough plasma concentrations are significantly increased from Day 7 (2.97 +/- 0.45 mg/l) to Day 9 (5.41 +/- 0.90 mg/l) and reach the steady state faster than it can be expected from half-life (40 hours) and dosing interval (24 hours). Elimination is faster (T1/2 beta = 37.14 +/- 3.18 h) after chronic regimen. Area under curve during dosing interval at steady state (164.19 +/- 21.70 mg.h/l) is significantly lower than the area under curve between zero and infinity in the single dose sequence (224.93 +/- 27.79 mg.h/l). These results agree with probable induction effect of chlormezanone on its own metabolism.

Central anticholinergic syndrome after ofloxacin overdose and therapeutic doses of diphenhydramine and chlormezanone.

A 14-year-old female with no history of psychiatric disease ingested an unknown amount of ofloxacin, diphenhydramine and chlormezanone after an argument with her patients. Approximately 12 hours after ingestion, the patient was admitted to the hospital in a delirious state with extreme mydriasis and warm and dry skin. Analytical data on admission were consistent with ofloxacin overdose and ingestion of therapeutic doses of diphenhydramine and chlormezanone. The patient received activated charcoal and forced diuresis was instituted. Psychosis and anticholinergic symptoms lasted in the next 2 days. On day 3, the psychotic and anticholinergic symptoms were nearly completely reversed by 2 mg physostigmine salicylate, given IV x 2. Since anticholinergic symptoms have not been observed after ofloxacin overdose or after therapeutic doses of diphenhydramine or chlormezanone, this case suggests a potentiation of the anticholinergic effects of diphenhydramine and chlormezanone by ofloxacin overdose.

Determination of chlormezanone in human plasma after administration of chlormezanone formulations.

In the course of a bioavailability study some 800 plasma samples were analysed by means of HPLC after administration of 5 different chlormezanone formulations to 10 healthy male volunteers. A metabolic product of chlormezanone (I) could not be detected in any of the samples. The results were further verified through mass spectrometric measurements of chlormezanone, extracted from the plasma sample and separated through HPLC, in off-line mode. Chlormezanone is found as an intact molecule in human plasma samples.

Metabolism of chlormezanone in man.

The metabolism of chlormezanone (Muskel Trancopal) in man was studied by the aid of gas chromatography/mass spectrometry and high performance liquid chromatography after an oral dose of 400 mg. Six metabolites and/or degradation products were identified in the urine. Some of the metabolites are formed at least partially by nonenzymatic hydrolysis in the stomach. In contrast to previous publications, no unchanged drug was detected in plasma and urine. The main metabolite in plasma is generated by cleavage of the amide bond in the six-membered heterocyclic ring. This derivative is easily formed by in vitro hydrolysis at pH 1, too. It structurally resembles baclofene. About 40% of the dose is excreted with the urine. The major metabolite in urine is 4-chlorohippuric acid. Additionally, 4-chloro-benzoyl-N-methylamide, 4-chlorobenzoic acid, N-methylimino-4-chlorobenzaldehyde, 4-chlorobenzaldehyde, and "hydrolized" chlormezanone were identified.

Sensitive and selective method for the determination of chlormezanone in plasma by electron-capture gas chromatography.

A sensitive and selective determination method of chlormezanone in plasma has been divised. Chlormezanone in plasma was extracted with toluene at pH 4.5, and converted into p-chlorobenzaldehyde in 0.1 N NaOH. Using p-bromobenzaldehyde as an internal standard, the hydrolysis product and the internal standard were extracted with n-hexane, and the extract was concentrated in vacuo in the presence of isoamyl alcohol to prepare the sample solution. The sample solution was submitted to electron-capture gas chromatography. Chlormezanone was determined by use of the peak height ratio of p-chlorobenzaldehyde against the internal standard. The method was utilized successfully for pharmacokinetic studies of chlormezanone in plasma.