Document Details

Document Type:   Dissertation
Title:   The Role ofCYP3a4 and CYP2d6 Polymorphism in Unexpected Methadone Fatality
Author:   Lauren Richards Waugh
College:   Joan C. Edwards School of Medicine
Degree Program:   Biomedical Sciences, Ph.D.
Degree:   Doctor of Philosophy
Committee Director:   Gary O. Rankin, Ph.D.
Document Availability:   Document available for World-Wide access.
Date of Defense:   04/16/2010

West Virginia and Kentucky rank among the top 10 states for highest increase in methadone poisoning deaths from 1999 to 2004. Patients taking methadone, following the direction of a doctor, have unexpectedly died due to methadone overdose. Methadone is difficult to administer safely because the pharmacokinetics of the drug exhibit extreme interindividual variability. This variability in pharmacokinetics could be due to genetic variation of the two main cytochrome P450 enzymes (CYP3A4 and CYP2D6) responsible for the metabolism of methadone to its principal metabolite 2-ethyl-1,5-dimethyl-3,3 diphenylpyrrolidine (EDDP), which is pharmacologically inactive. The purpose of this study was to determine the possible role of CYP3A4 and CYP2D6 genetic polymorphisms in unexpected methadone fatality. A study cohort of 228 individuals who had died due to a methadone overdose were genotyped for 12 single nucleotide polymorphisms (SNPs) within the genes for CYP3A4 and CYP2D6. Of the 228 methadone overdoses, 136 were methadone-only and the remaining 92 were combined methadone/benzodiazepine overdoses. The differences between the observed genotypic frequencies were compared to the expected genotypic frequencies. None of the CYP2D6 SNPs were present at an increased frequency within the study population compared to the general Caucasian population. The CYP3A4 gene had two SNPs (rs2242480 and rs2740574) that were enriched within the study group. This enrichment was more significant in the methadone only overdoses. Kruskal-Wallis analysis of the methadone levels and methadone/EDDP ratios revealed there was not any single SNP associated with a significant increase in mean methadone level or mean methadone/EDDP ratio. A comparison of methadone levels for all 12 SNPs combined showed a steady increase in mean methadone levels in the study cases as the number of polymorphisms carried by the individuals increased. The findings of this study indicate that there may be two key SNPs on the CYP3A4 gene that cause or are associated with the poor metabolizer phenotype for methadone. Findings also indicate that a combination of SNPs on CYP3A4 and CYP2D6 genes could collectively cause an increased likelihood of unexpected methadone fatality. 

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