Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole

Centerholt, Carina; Ekblom, Maria; Odergren, Tomas; Borgå, Olof; Popescu, G; Molz, K. H.; Couturier, Andrea; Weil, Angelika

doi:10.1007/s00228-003-0598-y

Cited by 8 publications

(8 citation statements)

References 16 publications

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“…Inactivation in HLM by CMZ was relatively efficient as determined by k inact /K I ratio of 8.8 ml min 21 nmol 21 (Table 2), and this was primarily a function of its relatively high k inact value, similar to values reported for tienilic acid/CYP2C9, ticlopidine/ CYP2B6, and ritonavir/CYP3A (Obach et al, 2007). Results using rCYP2E1 gave essentially identical values as those found with HLM (Table 2), demonstrating CYP2E1 inactivation occurs without requirement of metabolism by other cytochromes known to metabolize CMZ (Centerholt et al, 2003). The selectivity of CMZ inhibition of CYP2E1 has been partially investigated in vitro and in vivo.…”

Section: Discussionsupporting

confidence: 75%

“…plasma concentrations occur approximately 1 hour after administration, with an elimination half-life of about 4 hours (Rätz et al, 1999). Clearance is hepatic blood-flow limited and occurs primarily through metabolism by CYP2A6, CYP3A4/5, and CYP2B6 (Centerholt et al, 2003) and CYP2E1 (data not shown). Compared with drugfree volunteers, the AUC of chlorzoxazone, given in a 250-mg dose, increased 3.4-fold in alcoholic patients receiving daily 1.2-2.4 g CMZ at least 1-3 days before chlorzoxazone (Eap et al, 1998).…”

mentioning

confidence: 96%

“…The pharmacokinetics of CMZ is well documented by multiple clinical studies (Rätz et al, 1999;Centerholt et al, 2003;Wilby and Hutchinson, 2004 and references therein). With oral dosing, peak Fig.…”

mentioning

confidence: 99%

“…The analogous mechanism for CMZ and CYP2E1 would be less operative here because the reversible inhibition constant was 21 mM (Table 1) and because of the strict requirement for NADPH to elicit potent inhibition. Accordingly, metabolites of CMZ (Centerholt et al, 2003) might be more apt to fit this model. The chloro-ethyl side chain of CMZ may also be involved in inactivation in a mechanism similar to that observed with alkanes (Guengerich, 2001).…”

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confidence: 99%

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Selective Time- and NADPH-Dependent Inhibition of Human CYP2E1 by Clomethiazole

Stresser

Perloff

Mason

et al. 2016

Drug Metabolism and Disposition

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The sedative clomethiazole (CMZ) has been used in Europe since the mid-1960s to treat insomnia and alcoholism. It has been previously demonstrated in clinical studies to reversibly inhibit human CYP2E1 in vitro and decrease CYP2E1-mediated elimination of chlorzoxazone. We have investigated the selectivity of CMZ inhibition of CYP2E1 in pooled human liver microsomes (HLMs). In a reversible inhibition assay of the major drug-metabolizing cytochrome P450 (P450) isoforms, CYP2A6 and CYP2E1 exhibited IC 50 values of 24 mM and 42 mM, respectively with all other isoforms exhibiting values >300 mM. When CMZ was preincubated with NADPH and liver microsomal protein for 30 minutes before being combined with probe substrates, however, more potent inhibition was observed for ). The K I and k inact values, along with other parameters, were used in a mechanistic static model to explain earlier observations of a profound decrease in the rate of chlorzoxazone elimination in volunteers despite the absence of detectable CMZ in blood.

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Section: Discussionsupporting

confidence: 75%

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confidence: 96%

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confidence: 99%

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confidence: 99%

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Selective Time- and NADPH-Dependent Inhibition of Human CYP2E1 by Clomethiazole

Stresser

Perloff

Mason

et al. 2016

Drug Metabolism and Disposition

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“…Patients with moderate/severe liver impairment have reported plasma clearance values approaching 50% of healthy patients (1).…”

Section: Contraindicationsmentioning

confidence: 99%

The Pharmacology of Chlormethiazole: A Potential Neuroprotective Agent?

Wilby

Hutchinson

2004

CNS Drug Reviews

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Chlormethiazole is a thiazole derivative with a long history of use as a sedative agent. The mode of action of the drug has been partly worked out and has been established with recognition that its mechanism of action involves potentiation of GABA activity, the major intrinsic inhibitory neurotransmitter. Animal models of stroke ranging from rodents to primates have suggested an optimistic role for chlormethiazole in preventing both anatomical and functional deleterious effects of stroke. Phase III clinical trials, therefore, proceeded but unfortunately with very little success. Recently, the animal models have been revisited in an attempt to identify causes for this discrepancy between the results from preclinical and clinical studies. This review studies the pharmacological roots of chlormethiazole from its origin through to its licensed and novel applications. Emphasis is placed on discussing the animal experiments which led to its grooming as a neuroprotective agent and also on the human trials. The review seeks to explain the discrepancies between animal and human studies, which include short survival times of experimental subjects, speed of drug administration and fundamental differences between species. The primate model of stroke perhaps offers the nearest alternative to phase III trials and has recently been used to compare a number of newer neuroprotective agents with greater efficacy than chlormethiazole. In addition, novel approaches involving human neurochemical analyses in vivo are described which may help bridge the gap between animal models and future phase III trials.

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Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease

2007

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More than 70% of alcohol is consumed by 10% of the population in the United States. Implicit in this statistic is that tremendous variation in the pattern of drinking (quantity, frequency, and duration) exists among alcohol consumers. Individuals who are binge or chronic drinkers will have different health outcomes than social drinkers. Therefore, knowing the pattern of drinking will shed light on how severely individuals are alcohol-dependent and on the extent of liver damage. Thus, these parameters assume particular relevance for the treatment-providing physician. Genetic factors contribute substantially to differences in alcohol metabolism. Variations in the activities of the alcohol-metabolizing enzymes, cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase, in part determine blood alcohol concentration, thereby contributing to the predisposition to becoming alcohol-dependent and to susceptibility to alcohol-induced liver damage. Chronic alcohol consumption induces cytochrome P450 2E1, a microsomal enzyme that metabolizes alcohol at high concentrations and also metabolizes medications such as acetaminophen and protease inhibitors. Alcohol metabolism changes the redox state of the liver, which leads to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The quantity and frequency of alcohol consumption severely impact the liver in the presence of comorbid conditions such as infection with hepatitis B or C and/or human immunodeficiency virus, type 2 diabetes, hemochromatosis, or obesity and thus have implications with respect to the extent of injury and response to medications. Conclusion: Knowledge of the relationships between the quantity, frequency, and patterns of drinking and alcoholic liver disease is limited. A better understanding of these relationships will guide hepatologists in managing alcoholic liver disease.

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Pharmacokinetics and sedative effects in healthy subjects and subjects with impaired liver function after continuous infusion of clomethiazole

Abstract: The reduced clomethiazole clearance in patients with moderate/severe liver impairment seems to call for a reduction of clomethiazole dosage. However, sedation was not observed in this group at the investigated dose level.

Cited by 8 publications

References 16 publications

Selective Time- and NADPH-Dependent Inhibition of Human CYP2E1 by Clomethiazole

Selective Time- and NADPH-Dependent Inhibition of Human CYP2E1 by Clomethiazole

The Pharmacology of Chlormethiazole: A Potential Neuroprotective Agent?

Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease

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