Drug Analysis Laboratory, Forensic Science Division, Supreme Prosecutors Office, Seoul, Korea.

Carisoprodol (CSP) is a musculoskeletal relaxant whose active metabolite is meprobamate (MPB). This drug has recently been noticed to be abused as an inexpensive alternative to illicit drugs in Korea. A method using solid-phase extraction (SPE) and gas chromatography/mass spectrometry (GC/MS) was developed for the determination of CSP and MPB in human hair. Hair samples (30 mg) were washed with distilled water and acetone, cut into small fragments (<1 mm), incubated in 1.0 M HCl overnight at 50 degrees C, and then adjusted to pH 6.5. The drugs were extracted from the resulting hydrolyzed solutions using a SPE column. The eluents were evaporated to dryness, then derivatized using N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) with 1% trimethylchlorosilane (TMCS) at 120 degrees C for 30 min. The derivatized extract (1 microL) was injected into the GC/MS system. Recoveries were in the range of 91.5-93.1% for CSP and 85.5-93.0% for MPB. The linear ranges were 0.5-10.0 ng/mg for both CSP and MPB with good correlation coefficients (r(2) = 0.995). The intra-day precision and accuracy ranged from 1.5 to 9.3% and -17.5 to 3.6%, respectively, and the inter-day precision and accuracy ranged from 3.9 to 6.2% and -15.0 to -3.9%, respectively. The limits of detection for CSP and MPB were 0.13 and 0.12 ng/mg, respectively. The applicability of the method was proven by analyzing a hair sample from an authentic abuser. Copyright (c) 2005 John Wiley & Sons, Ltd.

Simple pharmacological test battery to assess efficacy and side effect profile of centrally acting muscle relaxant drugs.

INTRODUCTION: Centrally muscle relaxants (CMRs) are used mainly for treating muscle spasticities of neurological origin, and painful muscle spasms due to rheumatologic conditions. Their use is frequently associated with dose-limiting adverse effects. New drugs with improved side-effect characteristics are badly needed. However, there is no general agreement in the pharmacological literature on what methods are adequate to assess CMR effect and side effects in behaving rodents, which may hinder the development of new drugs. Here we report on the establishment of a simple pharmacological test battery, which was used to compare efficacies and side effect profiles of 11 compounds with central muscle relaxant action, in mice (intraperitoneal application). METHODS: For measuring muscle relaxant activity, (1) a new tremor model (GYKI 20039-induced tremor) and (2) the morphine-induced Straub-tail assay were used. The former, newly developed method has advantages over harmaline- or LON-954-induced tremor. For detecting side effect liability (ataxia, sedation, impairment of voluntary motor functions), (1) the rota-rod test, (2) measurement of spontaneous motility, (3) the weight-lifting test and (4) the thiopental sleep test were used. RESULTS: Among the 11 muscle relaxant compounds tested (tolperisone, eperisone, silperisone, diazepam, baclofen, tizanidine, afloqualon, mephenesin, zoxazolamine, memantine and carisoprodol), the calculated safety ratios (i.e. ID50 for side effect/ID50 for muscle relaxant effect) varied in a wide range. Silperisone seems to have the most advantageous profile (safety ratios range between 1.7 and 3.3 in the different pairs of assays) compared to the other tested drugs with lower (one or more ratios below 1.5, and often far below 1) and more varying ratios. DISCUSSION: Therapeutic indices calculated from the results of these in vivo experiments for the clinically used muscle relaxants are in agreement with their adverse effect profiles in humans. Thus the present test battery seems to be suitable for predicting the possible clinical utility of newly synthesized compounds.

The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects.

AIMS: The aim of the present study was to investigate if subjects with one normal and one non-functional CYP2C19 allele (intermediate metabolizers; IMs) metabolized carisoprodol differently than individuals with two normal CYP2C19 alleles (extensive metabolizers; EMs) We also wanted to investigate whether the use of oral contraceptives influences the metabolism of carisoprodol in EMs and IMs. Impairing effects on psychomotor coordination and feelings of sedation were studied by comparing IMs with EMs following their ingestion of a single dose of 700 mg carisoprodol. METHODS: Thirty-seven healthy Caucasian volunteers participated in the study, of whom 25 were not using any drugs known to interact with CYP2C19, including two poor metabolizers (PMs) (CYP2C19 *2/*2 or CYP2C19 *2 /*4), 11 IMs (CYP2C19 *1/*2 or CYP2C19 *1/*4) and 12 EMs (CYP2C19 *1/*1); the remaining 12 participants were six EMs and six IMs using oral contraceptives. A single oral dose of 700 mg of carisoprodol was given, and blood drug concentrations were followed for 11 h and 45 min. During this time period, different pharmacodynamic measurements were made. RESULTS: IMs had a longer elimination half life (T(1/2)) (127 min; 95% confidence interval (CI) 95, 159) than EMs (96 min; 95% CI 84, 107) and a larger area under the concentration-time curve from 0 to infinity (AUC(0-infinity)) for carisoprodol (16.3 microg h ml(-1) ; 95% CI 11.9, 20.7) than EMs (11.3 microg h ml(-1) ; 95% CI 7.8, 14.8). The use of oral contraceptives was accompanied by larger AUC(0-infinity) for carisoprodol in both EMs (18.5 microg h ml(-1); 95% CI 10.7, 26.3) and IMs (26.0 microg h ml(-1) ; 95% CI 18.8, 33.2). EMs using oral contraceptives also had a longer T(1/2) (117 min; 95% CI 92, 143) and higher maximum carisoprodol concentration than EMs not using oral contraceptives. No significant differences in pharmacodynamic parameters were found between subjects in the different genotype groups or between users and non-users of oral contraceptives. CONCLUSIONS: Subsequent to a single-dose administration of carisoprodol, the carisoprodol AUC was approximately 45% larger in CYP2C19 IMs than in EMs. The use of oral contraceptives increased the AUC by approximately 60% in both EMs and IMs. Despite these pharmacokinetic effects, no significant differences with respect to the CYP2C19 IM and EM genotypes were observed in the acute impairing effects of a single dose of carisoprodol.

Human pharmaceuticals, hormones, and personal care product ingredients in runoff from agricultural fields irrigated with treated wastewater.

Irrigation of crops with treated wastewater has the potential to introduce effluent-derived organic microcontaminants into surface waters through agricultural runoff. To determine whether compounds indicative of the presence of treated effluent in irrigation water could be identified in agricultural runoff, surface runoff samples collected from effluent-irrigated and rain-fed cultivated fields were analyzed for a broad spectrum of organic compounds. A variety of compounds was identified that appeared to be associated with irrigation with treated wastewater. These compounds included human pharmaceuticals (e.g., carbamazepine, gemfibrozil, carisoprodol), personal care product ingredients (e.g., insect repellent, polycyclic musks), and alkyl phosphate flame retardant chemicals. Most of these compounds appear not to have been previously reported in agricultural runoff. These compounds were present at concentrations below the few published aquatic toxicology data available; however, their potential to elicit more subtle effects in aquatic organisms cannot be excluded. None of these compounds were detected by broad-spectrum analysis in samples from the same fields during runoff-producing rain events.

Carisoprodol intoxications and serotonergic features.

The symptoms and signs of carisoprodol intoxications do not resemble those caused by its metabolite meprobamate. Meprobamate most probably produces its effects through the GABAergic neurotransmitter system. The signs and symptoms of carisoprodol intoxications, however, are not easily explained by interaction with this neurotransmitter system. In the present study, four cases of carisoprodol intoxications are presented with emphasis on the presence of serotonergic signs and symptoms. All four cases fulfilled three different sets of criteria for the diagnosis of serotonin syndrome. These findings could indicate that an increased serotonin level in the central nervous system could explain some of the symptoms and signs of carisoprodol intoxications. This may have implications for the clinical evaluation and treatment of such intoxications. Since few laboratories routinely screen for carisoprodol it is important to keep this drug in mind when encountering intoxications displaying serotonergic symptoms.