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Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.
Neuropharmacology. 2020 Sep 01; 174:108152.N

Abstract

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.

Authors+Show Affiliations

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107-2699, USA.Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107-2699, USA.Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107-2699, USA.Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107-2699, USA.Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107-2699, USA. Electronic address: Laszlo.Prokai@unthsc.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32479814

Citation

Carbonaro, Theresa M., et al. "Carisoprodol Pharmacokinetics and Distribution in the Nucleus Accumbens Correlates With Behavioral Effects in Rats Independent From Its Metabolism to Meprobamate." Neuropharmacology, vol. 174, 2020, p. 108152.
Carbonaro TM, Nguyen V, Forster MJ, et al. Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate. Neuropharmacology. 2020;174:108152.
Carbonaro, T. M., Nguyen, V., Forster, M. J., Gatch, M. B., & Prokai, L. (2020). Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate. Neuropharmacology, 174, 108152. https://doi.org/10.1016/j.neuropharm.2020.108152
Carbonaro TM, et al. Carisoprodol Pharmacokinetics and Distribution in the Nucleus Accumbens Correlates With Behavioral Effects in Rats Independent From Its Metabolism to Meprobamate. Neuropharmacology. 2020 Sep 1;174:108152. PubMed PMID: 32479814.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate. AU - Carbonaro,Theresa M, AU - Nguyen,Vien, AU - Forster,Michael J, AU - Gatch,Michael B, AU - Prokai,Laszlo, Y1 - 2020/05/29/ PY - 2019/10/10/received PY - 2020/04/29/revised PY - 2020/05/18/accepted PY - 2020/6/2/pubmed PY - 2020/6/2/medline PY - 2020/6/2/entrez KW - Carisoprodol KW - Distribution KW - Drug discrimination KW - Metabolism KW - Pharmacokinetics KW - Rat SP - 108152 EP - 108152 JF - Neuropharmacology JO - Neuropharmacology VL - 174 N2 - 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/32479814/Carisoprodol_pharmacokinetics_and_distribution_in_the_nucleus_accumbens_correlates_with_behavioral_effects_in_rats_independent_from_its_metabolism_to_meprobamate L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(20)30220-3 DB - PRIME DP - Unbound Medicine ER -
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