CYP2C19 genetics in fatal carisoprodol intoxications
Abstract
Introduction
Carisoprodol, a frequently used muscle relaxant, can cause potentially fatal intoxications. Conversion to its active metabolite meprobamate is almost solely mediated by cytochrome P450 2C19 (CYP2C19), and mutations in this enzyme could have significant effects on serum concentrations. The objective of this study was to investigate the role of CYP2C19 genetics in mortalities due to carisoprodol intoxication.
Methods
The frequencies of CYP2C19 variant alleles were compared between the study group (n = 75) and two control groups, i.e. (1) deaths where carisoprodol was detected in the blood of the deceased, but intoxication was not the cause of death (control group A, n = 38), and (2) a healthy population not using carisoprodol (control group B, n = 185). In the study group and control A, the concentrations of carisoprodol and meprobamate were compared between the different genotype subgroups.
Results
The variant allele frequencies of CYP2C19 did not differ significantly between the study group and control groups. Moreover, no statistically significant difference in the concentrations of carisoprodol and meprobamate between the different genotype subgroups was found.
Conclusions
This study finds no evidence for an important association between CYP2C19 genetics and mortality risk of carisoprodol. Other factors, such as co-administration with other drugs, likely play a more important role.
Keywords
Carisoprodol Meprobamate CYP2C19 variant alleles IntoxicationNotes
Acknowledgements
The authors are grateful to Eleni Aklillu for providing genotype frequencies in control group B and to Asbjørg Christophersen and Ritva Karinen for organising the blood samples. We also thank Linda Uthus and Ida Mari Haugom for genotyping the postmortem samples.
Reference
- 1.Boyles W, Glassmann J, Soyka J (1983) Management of acute muskuloskeletal conditions: thoracolumbar strain and spain. A double-blind evaluation comparing the efficacy and safety of carisoprodol with diazepam. Today’s Ther Trends 1:1–16Google Scholar
- 2.Bailey DN, Briggs JR (2002) Carisoprodol: an unrecognized drug of abuse. Am J Clin Pathol 117:396–400PubMedCrossRefGoogle Scholar
- 3.Bramness JG, Morland J, Sorlid HK, Rudberg N, Jacobsen D (2005) Carisoprodol intoxications and serotonergic features. Clin Toxicol (Phila) 43:39–45Google Scholar
- 4.Hoiseth G, Sorlid HK, Bramness J (2008) Acute intoxications with carisoprodol. Clin Toxicol (Phila) 46:307–309CrossRefGoogle Scholar
- 5.Backer RC, Zumwalt R, McFeeley P, Veasey S, Wohlenberg N (1990) Carisoprodol concentrations from different anatomical sites: three overdose cases. J Anal Toxicol 14:332–334PubMedGoogle Scholar
- 6.Adams HR, Kerzee T, Morehead CD (1975) Carisoprodol-related death in a child. J Forensic Sci 20:200–202PubMedGoogle Scholar
- 7.Davis GG, Alexander CB (1998) A review of carisoprodol deaths in Jefferson County, Alabama. South Med J 91:726–730PubMedCrossRefGoogle Scholar
- 8.Winek CL, Wahba WW, Winek CL Jr, Balzer TW (2001) Drug and chemical blood-level data 2001. Forensic Sci Int 122:107–123PubMedCrossRefGoogle Scholar
- 9.Druid H, Holmgren P (1997) A compilation of fatal and control concentrations of drugs in postmortem femoral blood. J Forensic Sci 42:79–87PubMedGoogle Scholar
- 10.Hoiseth G, Bramness JG, Christophersen AS, Morland J (2007) Carisoprodol intoxications: a retrospective study of forensic autopsy material from 1992–2003. Int J Legal Med 121:403–409PubMedCrossRefGoogle Scholar
- 11.Bramness JG, Skurtveit S, Gulliksen M, Breilid H, Steen VM, Morland J (2005) The CYP2C19 genotype and the use of oral contraceptives influence the pharmacokinetics of carisoprodol in healthy human subjects. Eur J Clin Pharmacol 61:499–506PubMedCrossRefGoogle Scholar
- 12.Sim SC, Risinger C, Dahl ML, Aklillu E, Christensen M, Bertilsson L et al (2006) A common novel CYP2C19 gene variant causes ultrarapid drug metabolism relevant for the drug response to proton pump inhibitors and antidepressants. Clin Pharmacol Ther 79:103–113PubMedCrossRefGoogle Scholar
- 13.Ramsjo M, Aklillu E, Bohman L, Ingelman-Sundberg M, Roh HK, Bertilsson L (2010) CYP2C19 activity comparison between Swedes and Koreans: effect of genotype, sex, oral contraceptive use, and smoking. Eur J Clin Pharmacol 66:871–877PubMedCrossRefGoogle Scholar
- 14.Zackrisson AL, Holmgren P, Gladh AB, Ahlner J, Lindblom B (2004) Fatal intoxication cases: cytochrome P450 2D6 and 2C19 genotype distributions. Eur J Clin Pharmacol 60:547–552PubMedCrossRefGoogle Scholar
- 15.Zackrisson AL, Lindblom B, Ahlner J (2010) High frequency of occurrence of CYP2D6 gene duplication/multiduplication indicating ultrarapid metabolism among suicide cases. Clin Pharmacol Ther 88:354–359PubMedCrossRefGoogle Scholar
- 16.Bramness JG, Skurtveit S, Fauske L, Grung M, Molven A, Morland J et al (2003) Association between blood carisoprodol:meprobamate concentration ratios and CYP2C19 genotype in carisoprodol-drugged drivers: decreased metabolic capacity in heterozygous CYP2C19*1/CYP2C19*2 subjects? Pharmacogenetics 13:383–388PubMedCrossRefGoogle Scholar