Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.

Carisoprodol (Soma®) is a centrally-acting skeletal-muscle relaxant frequently prescribed for treatment of acute musculoskeletal conditions. Carisoprodol's mechanism of action is unclear and is often ascribed to that of its active metabolite, meprobamate. The purpose of this study was to ascertain whether carisoprodol directly produces behavioral effects, or whether metabolism to meprobamate via cytochrome P450 (CYP450) enzymatic reaction is necessary. Rats were trained to discriminate carisoprodol (100 mg/kg) to assess time course and whether a CYP450 inhibitor (cimetidine) administered for 4 days would alter the discriminative effects of carisoprodol. Additionally, pharmacokinetics of carisoprodol and meprobamate with and without co-administration of cimetidine were assessed via in vivo microdialysis combined with liquid-chromatography-tandem mass spectrometry from blood and nucleus accumbens (NAc). The time course of the discriminative-stimulus effects of carisoprodol closely matched the time course of the levels of carisoprodol in blood and NAc, but did not match the time course of meprobamate. Administration of cimetidine increased levels of carisoprodol and decreased levels of meprobamate consistent with its interfering with metabolism of carisoprodol to meprobamate. However, cimetidine failed to alter the discriminative-stimulus effects of carisoprodol. Carisoprodol penetrated into brain tissue and directly produced behavioral effects without being metabolized to meprobamate. These findings indicate that understanding the mechanism of action of carisoprodol independently of meprobamate will be necessary to determine the validity of its clinical uses.

Mass spectrometric analysis of carisoprodol and meprobamate in rat brain microdialysates.

We report the evaluation of several mass spectrometry-based methods for the determination of carisoprodol and meprobamate in samples obtained from the rat brain by in vivo intracranial microdialyis. Among the techniques that aspire to perform analyses without chromatographic separation and thereby increase throughput, chip-based nanoelectrospray ionization and the use of an atmospheric pressure solids analysis probe fell short of requirements because of insufficient detection sensitivity and hard ionization, respectively. Although direct analysis in real time provided the required soft ionization, shortcomings of a tandem mass spectrometry-based assay also included inadequate detection sensitivity and, in addition, poor quantitative reproducibility. Therefore, liquid chromatography coupled with atmospheric pressure chemical ionization tandem mass spectrometry was developed to determine carisoprodol and meprobamate from artificial cerebrospinal fluid as the medium. No desalting and/or extraction of the samples was necessary. The assay, combined with in vivo sampling via intracranial microdialyis, afforded time-resolved concentration profiles for the drug and its major metabolite from the nucleus accumbens region of the brain in rats after systemic administration of carisoprodol. Copyright © 2016 John Wiley & Sons, Ltd.

Carisoprodol withdrawal after internet purchase.

INTRODUCTION: Carisoprodol is a centrally acting muscle relaxant used in the treatment of various musculoskeletal disorders whose main metabolite, meprobamate, is a controlled substance in the United States due to its sedative properties and potential for abuse. CASE DESCRIPTION: We report a case of a 51-year-old man with cognitive impairment and tremor who developed worsening tremor, anxiety, myoclonus, ataxia, and psychosis on abrupt cessation of carisoprodol. At hospital discharge, his cognitive function significantly improved compared with when he was on carisoprodol. CONCLUSION: Carisoprodol withdrawal is an important and under-recognized syndrome that should be considered in patients presenting with neurologic symptoms who are taking the medication. Carisoprodol withdrawal can be successfully treated with the use of benzodiazepines, although further studies are needed to identify the most appropriate treatment protocol.

Is the frequency of carisoprodol withdrawal syndrome increasing?

Carisoprodol is a commonly used centrally acting muscle relaxant. A number of case reports have suggested that the drug may have abuse potential, presumably because it is metabolized to the anxiolytic drug, meprobamate, which is a controlled substance at the federal level. Two recent case reports described symptoms of withdrawal after the cessation of carisoprodol. We present two additional cases that support the concept of a withdrawal syndrome with this drug. Symptoms of carisoprodol withdrawal include anxiety, tremulousness, insomnia, jitteriness, muscle twitching, and hallucinations. These symptoms are most likely caused by withdrawal from the meprobamate that accumulates after large amounts of carisoprodol are ingested. Although carisoprodol is not a controlled substance at the federal level, clinicians should be aware of its significant potential for abuse.

Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects?

Carisoprodol is metabolized to meprobamate by the cytochrome P450 enzyme CYP2C19, encoded by the polymorphic CYP2C19 gene. Most studies on carisoprodol metabolism have been carried out on individuals phenotyped for CYP2C19 activity using the probe drug S-mephenytoin. We aimed to investigate whether the ratio of carisoprodol to meprobamate in a 'real life' setting could be predicted by CYP2C19 genotype or, more specifically, if high carisoprodol : meprobamate ratios in drugged drivers could be ascribed to the presence of mutant CYP2C19 alleles. From original material comprising 358 blood samples from apprehended drivers, two polarized groups were selected; a high-ratio group of 11 subjects where the carisoprodol : meprobamate ratio was >1 and a low-ratio control group of 23 subjects where the ratio was <0.31. Genotyping was carried out for the CYP2C19*2, CYP2C19*3 and CYP2C19*4 alleles. DNA samples from 94 healthy blood donors were used as reference material. The number of mutant alleles in the high-ratio and low-ratio groups was significantly higher and lower, respectively, than in the reference material. The increased number of mutant alleles in the high-ratio group was not due to the presence of many poor metabolizers, but to a high number of heterozygous individuals with the genotype CYP2C19*1/*2. This result indicates a gene dosage effect where the carisoprodol : meprobamate ratio reflects the number of active CYP2C19 alleles. The metabolism of carisoprodol to meprobamate is dependent on CYP2C19 genotype. Heterozygous individuals with the CYP2C19*1/*2 genotype have a reduced capacity for metabolizing carisoprodol, and should probably be regarded as intermediate metabolizers of this drug.

Tranquilizers, analgetics and antidepressants in patients treated with hemodialysis.

Tranquilizers, analgetics and antidepressants are applied in different ranges in the treatment of patients on hemodialysis. Due to many different pharmacokinetic properties, no perfect rules for dosage in acute or chronic hemodialysis exist. Adequate applicable drugs without adaptation disregarding different states of renal failure are such with predominate hepatic metabolism and elimination or with inactive metabolites. In the management of acute renal failure, usually in connection with multiple organic disorders, a nonschematic, individually adapted therapy is indicated. In some substances, therapy can be determined by control of plasma concentration levels, in other drugs dosage is possible exclusively according to clinical effects. Substances with side effects on coagulation or acid-base equilibrium should be avoided. It is recommendable to get well acquainted with one substance out of each group in order to avoid polypragmasy.

The pharmacokinetics of meprobamate following its oral and rectal administration as a series of combinations with diphenhydramine, acetylsalicylic acid, codeine and pentaerythritol tetranitrate.

Studies in human volunteers of the pharmacokinetics of the active drugs in the formulations Visano-mini (meprobamate and diphenhydramine HCl), DoloVisano (meprobamate, diphenhydramine HCl, acetylsalicylic acid and codeine phosphate) and VisanoCor (meprobamate, diphenhydramine HCl and pentaerythritol tetranitrate (PETN], have demonstrated systemic absorption of each of the drugs from all of the formulations. Bioequivalence of meprobamate is indicated despite the drug combinations involved. Some differences in diphenhydramine pharmacokinetics are, however, apparent. The bioavailability of meprobamate administered rectally to human volunteers as the marketed preparations DoloVisano Suppositories and Dolo-Visano Suppositories sine codeino, is similar to that observed following oral administration.

[Respective roles of gastric lavage, haemodialysis, haemoperfusion, diuresis and hepatic metabolism in the elimination of a massive meprobamate overdose (author's transl)]. / Part respective du lavage gastrique, de l'hémodialyse, de l'hémoperfusion, de la diurèse et du métabolisme hépatique dans l'épuration du méprobamate.

A case of massive meprobamate intoxication (100 g) is reported. On admission, 8 hours later, the plasma meprobamate level was 460 mg/l. The initial shock (hours 8-12) was successfully treated with blood volume expansion and dobutamine. The plasma meprobamate level, which was 340 mg/l when haemodialysis and haemoperfusion were started, fell to 110 mg/l at the end of the treatment. Recovery was uneventful. The amounts of drug eliminated by each method were as follows: (a) gastric lavages at 8 and 26 hours: 66 g; (b) haemodialysis (18-29 hours): 8.5 g; (d) haemoperfusion on Hemopur-charcoal (20-28 hours): 7.5 g (as measured by elution); (e) diuresis (26 hours): 2 g. It may be concluded from these data that sizeable amounts of drug can be extracted by haemodialysis and haemoperfusion, that gastric lavage remains the least invasive and most rewarding method of elimination, and that the role of hepatic metabolism in detoxication has to be taken into account.

Acute metabolic interaction of ethanol and drugs.

Addition of ethanol in vitro was found to inhibit the microsomal metabolism of a variety of drugs such as meprobamate, aminopyrine, pentobarbital and zoxazolamine. In all cases, a mixed type of inhibition was obtained. When the concentration of alcohols of different chain lengths required to inhibit 50% of the metabolism of drugs was plotted against their corresponding octanol-water partition coefficients (Po/w) it was found that the inhibitory potency of alcohols is linearly related to the partition coefficients, with a slope of 0.98. In vivo acute administration of ethanol also resulted in decreased whole body metabolism of meprobamate, aminopyrine, pentobarbital, zoxazolamine and aniline. In vitro addition of pentobarbital, phenobarbital and meprobamate had no significant effect on ethanol metabolism by liver slices. Acute pretreatment with these drugs also had no effect on the rate of ethanol metabolism in vivo as measured in the whole body or as estimated from the rate of decrease of blood ethanol concentration. It appears therefore that acute metabolic interaction of ethanol and drugs is a one sided phenomenon, i.e. ethanol inhibits drug metabolism, whereas drugs do not inhibit ethanol metabolism. Ethanol inhibition of drug metabolism in vitro appears to result from a modification of the lipophilic milieu that surrounds the cytochrome P-450 in the microsomal membrane. Interference with the hydrophobic sites may either directly or indirectly affect the catalytic activities of the microsomal enzyme.

Drug kinetics and alcohol ingestion.

Acute and chronic ethanol ingestion can alter both the pharmacodynamics and pharmacokinetics of other drugs. For psychotherapeutic drugs, modification of drug action by alcohol is much more important than kinetic interaction, such as ethanol induced drug metabolism. In contrast, the importance of the effects of alcohol on the kinetics of other classes of drug is incomplete. The probability and mechanism of alcohol kinetic interactions with other drugs can nevertheless be anticipated, in part, on the basis of the extent of binding of the drug to plasma proteins, the capacity of the liver for extracting the drug from blood passing through the liver and the true distribution space of the drug. Highly bound drugs with low intrinsic hepatic clearance are among the most commonly reported to have their kinetics altered by ethanol (e.g. benzodiazepines, phenytoin, tolbutamide and warfarin). Less highly bound drugs are less consistently affected (e.g. meprobamate, glutethimide, pentobarbitone and phenobarbitone). Acute administration of ethanol to laboratory animals or incubation of microsomal preparations with ethanol inhibits the mixed function oxidase activity. In the human, the elimination half-life of meprobamate, pentobarbitone and tolbutamide is increased by acute ethanol administration. Chronic administration of ethanol to rats and humans causes proliferation of the smooth endoplasmic reticulum, increase in microsomal protein content and cytochrome P450 and results in an augmentation in drug metabolising ability of the microsomes in vitro. Even though the plasma half-life of some drugs is decreased by chronic ethanol ingestion, the clinical determination of the mechanism is incomplete because few studies have measured drug metabolite levels. In addition, alcohol effects on drug distribution have not been studied very extensively. The effects of chronic alcohol ingestion on drugs with low and high hepatic extraction, high and low binding, important tissue localisation and microsomal and non-microsomal metabolism will be quite different. Systematic studies of the mechanism of alcohol kinetic interactions are needed. Such kinetic studies should be combined with pharmacodynamic measures in order to establish the clinical importance of changes in drug kinetics.

Relative bioavailability of meprobamate tablets in humans.

The relative bioavailability of 400-mg meprobamate tablets manufactured by 11 different firms was evaluated in two groups of healthy male subjects. Each group of six subjects received a reference standard product and five test products given at 1-week intervals. Plasma meprobamate concentrations at 1, 2, 3, 4, 6, 8, 10, 24, and 32 hr after dosing were determined using a GLC assay. Analysis of variance of the plasma level--time profiles revealed no statistically significant differences between any of the products in terms of plasma levels at the various sample times, time of peak plasma level, peak plasma level, and area under the plasma level--time curve. It was concluded that the 11 400-mg products could be considered bioequivalent.

Secretion of drugs by the parotid glands of rats and human beings.

The following drugs have been demonstrated to be secreted by the parotid glands of rats and human beings: amobarbital, chlorpromazine, codeine, glutethimide, meprobamate, pentobarbital, phenobarbital, and secobarbital. Methadone could not be detected in the parotid saliva of either rats or human beings, and morphine has been demonstrated only in parotid saliva of rats.

Alteration of drug metabolism during cholestasis in man.

The morphological and functional alterations of the smooth endoplasmic reticulum of the liver cell related to biliary stasis have brought attention to drug biotransformation during cholestasis. The metabolism of meprobamate, pentobarbital and tolbutamide was assessed in subjects with intrahepatic recurrent cholestasis (3), cholestatic hepatitis (6), extrahepatic biliary obstruction (7) and normal controls (16). In the patients with recurrent intrahepatic cholestasis no differences in drug metabolism were noted as compared to the control group. In cholestatic hepatitis the plasma half-lives of meprobamate (828 +/- 422 min.) and pentobarbital (39+-65) were significantly longer than in in controls (444 +/- 37 and 25.4 +/- 1.1 respectively). Tolbutamide plasma half-life appeared unchanged. The most striking variations were observed in the patients with extrahepatic biliary obstruction. In such cases while meprobamate half-life was unchanged, pentobarbital half-life was significantly prolonged (31.2 +/- 2.5) and the in vitro metabolism of the drug, using liver preparations, was decreased to less than 50% of the control value. In contrast the metabolism of tolbutamide was accelerated as evidenced by a significant decrease of plasma half-life (165 +/- 48 min. versus 384 +/- 76 of the controls) and an enhanced urinary excretion of the drug's metabolites. However the metabolism of tolbutamide in vitro did not show any difference between normal and cholestatic liver. Whatever the mechanism of the peculiar behaviour of tolbutamide in extrahepatic biliary obstruction it seems to be related to the increased bile dalt concentration during cholestasis. In fact the low values of plasma half-life increase significantly either relieving the biliary obstruction or producing a bile salt depletion with cholestyramine. Preliminary results in vitro suggest the bile salt could displace tolbutamide from albumin binding thus increasing the amount of free drug available for biotransformation by the liver. In conclusion cholestasis may affect drug metabolism depending on the degree of biliary stasis, liver cell injury and the type of drug tested. The mechanism could be that of an impaired biotransformation in the smooth endoplasmic reticulum or could involve extrahepatic factors.

Drug interactions: the effects of alcohol and meprobamate applied singly and jointly in human subjects. I. Theoretical considerations and literature review.

The considerations necessary to describe the effects of combinations of drugs in a biological system are reviewed. The terms which express these effects-additive, potentiative, antagonistic, synergistic-have not had specific operations applied to them and mathematical models have been sought to define these operations. The models should (1) describe the nature of the action of single drugs, (2) classify the results of drug combinations, (3) provide a set of operations for deciding the outcome of combinations, and (4) predict all possible results of a combination from a knowledge of each drug acting alone. Research on the effects of alcohol and meprobamate and their interactions is reviewed, including behavioral and pharmacological studies and also some studies of the interaction of alcohol with other drugs. The task of characterizing the relation between the drug and response is formidable because complex physiological and biochemical processes determine the relationship between administered and effective dose and are further complicated by route of drug administration and various time relations. The descriptions of biochemical and physiological events seem well advanced; those of behavior are not. Much of the behavioral research assumes that a single dose is representative of all doses of the drug, and that combinations of the drugs and additivity of effects can be determined without a rigorous definition or means of application. [Bibliography of 249 items.]