EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS. 1991. Vol. 16. No. I, pp. 43-47

Chlormezanone plasma and blood levels in patients after single and repeated oral doses and after suicidal drug overdose 1 C. KOPPEL, J. KRISTINSSON2,A. WAGEMANN3,J. TENCZER3,and F. MARTENS 1

lReanimalionszentrum, KlinikumRudolfVirchow, Standort Charlottenburg, Freie Universitat Berlin, Germany 2Department ofPharmacology, University ofIceland, Reykjavik, Iceland _ 3Department ofToxicology, Landesuntersuchungsinstitutftlr Lebensmittel, AnneimittelundTierseuchen Berlin, Berlin, Germany Receivedfor publication: April 12, 1989 Keywords: Chlormezanone, clinical studies, plasma kinetics, single dose and repeated doses, fatal overdose

SUMMARY 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 J.Lg/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 J.Lg/ml (group 2) and 22.7 ± 4.0 J.Lg/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 J.Lg/ml. 8.9 ± 2.2 J.Lg/ml, 12.7 ± 2.0 ug/ml, and 10.4 ± 2.4 J.Lg/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. Chlormezanone is equally distributed between plasma and erythrocytes. In 3 cases of fatal drug overdose involving chlormezanone/diazepam (case I), chlormezanone/acetaminophen/diazepam (case 2), and chlormezanone/acetaminophen (case 3), chlormezanone blood levels amounted to 53,13 and 9 J.Lg/ml. respectively. Tissue levels were determined in addition.

INTRODUCTION Chlormezanone is a widely used muscle relaxant for oral application (e.g., Muskel-Trancopal@ Manufacturer: Winthrop, Norderstedt, FRG). It has been recommended alone or in combination with non-narcotic analgesics like acetaminophen for treatment of painful muscular spasms due to Please send reprint requests to : Dr Dr Claus KOppel, Reanimationszentrum, Klinikum Rudolf Virchow, Standort Charlottenburg, Freie Universitat Berlin, Spandauer Damm 130, n-rooo Berlin 19, FRG

degenerative skeletal disease. Chlonnezanone exerts its muscle relaxant effect by inhibiting polysynaptic reflex pathways in subcortical and spinal centres (1). It has only little sedative effect A daily oral dose of 2-3 x 200 mg which may be increased to 3 x 400 mg has been recommended (package circular of Muskel-Trancopal@). To our knowledge, plasma levels after repeated doses and a therapeutic plasma range have not yet been detennined. Urinary metabolism of chlonnezanone in humans has recently been studied by us (2). 4-Chlorohippuric acid, 4-chlorobenzoic acid, 4-chlorobenzaldehyde, N-methyl-4-chlorobenzamide and N-methyl-4-chloro-

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benzimine were identified in urine. A degradation product, but no unchanged chlormezanone, was detected in plasma of 2 volunteers after 200 mg of chlormezanone. However, in further studies, we were able to identify unchanged chlormezanone in plasma of patients on chlormezanone and in post-mortem blood samples of patients with fatal drug overdose. Similar findings have been reported by other authors after oral administration of different formulations of chlonnezanone to volunteers (3). In this study, we investigated chlormezanone plasma concentrations after single and repeated oral doses. Since little data on fatal chlormezanone poisoning have been published so far (4), post-mortem findings in 3 patients with fatal drug overdose including chlormezanone are presented in addition.

MATERIALS AND METHODS Materials Acetonitrile, Chrom AR@ (Mallinckrodt, Missouri, USA) was used for the high performance liquid chromatography (HPLC) assay without further purification. All other reagents were analytical grade. Reference compound of chlormezanone was obtained as a gift from Winthrop (Norderstedt, FRG). Its purity was checked by HPLC, gas chromatography/mass spectrometry and UV spectrophotometry.

High performance liquid chromatography A high performance liquid chromatograph consisting of a Rheodyne 7125 (20 ul loop), a pump 410, a diode array UV detector 235, and an LCI-1oo integrating recorder from Perkin Elmer (i)berlingen, FRG) was used for analysis. Column : 12 em x 0.4 em (i.d.) in combination with a precolumn 2 em x 0.4 cm (i.d.), both packed with Nucleosil CIS, 5 urn (Macherey & Nagel, DOren, FRG). Mobile phase: Acetonitrile 1 twice distilled water 1 ortho phosphoric acid 85% (3516510.1 : v/v/v); flow 1.5ml/min. Wave length: 225 om, for quantitation, peak purity control by UV spectra. Sample preparation : 0.2 ml plasma were mixed thoroughly with 0.3 ml acetonitrile, allowed to stand for 10 min, mixed again and then centrifuged for 5 min. The clear supernatant was used for HPLC

analysis. Standard stock solutions were prepared in methanol and diluted with the mobile phase. Recovery of chlormezanone added to blank plasma was 98% with a standard deviation of ± 3%. The detection limit under the described conditions was 0.05 J.1g/ml plasma. Chlonnezanone standard curves were linear within 0.2 to 35 J.1g/ml plasma. Analysis of whole blood and plasma samples yielded evidence that chlormezanone is equally distributed between plasma and erythrocytes.

Clinical studies Group 1 (single dose) After informed consent, 5 healthy volunteers (group 1) received an oral dose of 200 J:!1g chlormezanone (1 tablet of Muskel- Trancopal@). Blood was withdrawn after 0.5, 1, 2, 4, 8, 18, 32, 56 and 80 h from an antecubital vein. Heparinized blood samples were centrifuged and plasma stored at -20·C prior to analysis.

Groups 2 and 3 (repeated doses) 12 patients (group 2) with painful muscular spasms in the spinal region received a daily oral dose of 3 x 200 mg of chlormezanone (3 x 1 tablet of Muskel-Trancopal@). In another 10 patients (group 3) not responding sufficiently to 3 x 200 mg, the daily dose was increased to 3 x 400 mg of chlormezanone (3 x 2 tablets of Muskel-Trancopal@). Blood tests in all patients were normal with respect to liver and kidney function. Blood was withdrawn after 5 days of treatment before intake of the next dose. The sample was treated as described above. In 3 patients each of groups 2 and 3, 'chlormezanone plasma levels were determined in addition after 10 days of treatment. All patients of groups 2 and 3 were hospitalized for uncomplicated acute myocardial infarction and underwent a standard physiotherapeutic exercise programme. This programme included exercise in bed for the first 8 days and then stepwise progressive mobilization (modified 'Heidelberg' programme).

Group 4 (loading dose and repeated doses) In older to achieve steady-state chlormezanone plasma levels earlier than in group- 2, 5 patients received a loading dose of 800 mg and then repeated doses of 3 x 200 mg chlormezanone daily.

C. Koppel et al., Chlormezanone after oral doses/overdose

45

seen alert and awake the day before. A legal autopsy was performed, which revealed early stages of hepatic necrosis, mild pulmonary emphysema and a small ulcus ventriculi.

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Fig 1 : Chlormezanone plasma concentrations (mean values) after a single oral dose of 200 mg

Clinical studies

Post-mortem studies in patients with drug overdose

Single dose

Case 1 A 24 year old female from Iceland with a previous history of attempted suicide was found dead in her home, one day after she was last seen alive. Several days before she had obtained prescriptions from two different doctors for 100 tablets containing 200 mg chlormezanone, 100 tablets containing 2 mg of diazepam and 30 tablets containing 5 mg of nitrazepam. Upon her death, no diazepam tablets were left, whereas 46 chlormezanone tablets and 12 nitrazepam tablets were found in her room. A medicolegal autopsy was performed, which revealed no major organic lesions.

Case 2 A 46 year old male from Iceland with a histo~ of alcohol abuse ingested about 40 tablets of Lobak (= 4 g chlormezanone and 18 g acetaminophen) and an unknown amount of diazepam tablets (5 mg). About 24 h later, he was discovered in deep coma and admitted to hospital, where he died 35 h after admission. A medicolegal autopsy was performed, which revealed fatty infiltration and extensive necrosis of the liver. Extensive necrosis was also found in renal tubuli. Further findings included congestion of lungs, heart, pancreas and adrenal cortex.

Case 3 A 40 year old unemployed male was admitted to a hospital in Reykjavik. He was unconscious and died little more than one hour after admission. He was last

By least squares approximation, a chlormezanone plasma elimination half-life of 23 ± 2.3 h (mean ± standard deviation) was calculated for group 1 after a single dose (5). The area under the curve (AUC) was 57 ± 12 mg.hIl and the extrapolated Cmax was 2.0 /-lg/ml. Mean peak chlormezanone plasma levels reached 1.86 ± 0.2 ug/ml ! h after intake (Fig. 1).

Repeated doses After 5 days of a daily dose of 3 x 200 mg of chlormezanone, plasma levels of 12.0 ± 2.0 !J.g/ml (group 2), and after 3 x 400 mg of chlormezanone, 22.7 ± 4.0 ug/ml (group 3) were determined. Similar values were obtained after 10 days of treatment in 3 patients of each of the two groups. Trace amounts of the degradation product could be detected in plasma samples of all groups (retention time of chlormezanone, 4.12 min; retention time of the degradation product, 3.25 min).

Loading dose and repeated doses Chlormezanone plasma levels in group 4 were 6.5 ± 2.1 ug/ml, 8.9 ± 2.2 !J.g/ml, 12.7 ± 2.0 ug/ml, and 10.4 ± 2.4 !J.g/ml after 2,8, 16 and 36 h respectively. Although partial release of pain was reported by all patients, none of the patients was completely free of pain after chlormezanone monotherapy. Seven patients of group 3 complained about increasing muscular weakness, ataxia, stumbling and tachycardia inducible by physiotherapeutic exercise on the fifth day. The adverse effects disappeared within 2 days after discontinuation of the drug in these patients. Chlormezanone plasma levels of the 7 patients did not

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Table I : Toxicological findings in 3 cases of fatal drug overdose involving chlormezanone Case I

Case 2

Case 3

chlormezanone

bloodv brain

53 (J.L8Iml) 109 (p.g/g)

liver

88 (J.L8Ig)

urine

31 (J.L8Iml)

13 (p.g/ml) 25 (p.g/g) 23 (p.g/g)

9 (J.L8Iml) 16 (J.L8Ig) 28 (J.L8Ig) 104 (J.L8Iml)

diazepam blood 1.64 (J.L8Iml) nordiazepam 0.4 (p.g/ml) blood