Pharmacogenetics for rheumatic diseases = 류마티스 질환의 약물유전학 연구

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Pharmacogenetic studies on effectiveness and toxicity of various drugs have been performed widely for the personalized medication based on individual genetic information. In the present work, the genetic backgrounds for diverse responses of two drugs in treatments of osteoarthritis (OA) and systemic lupus erythematosus (SLE) were studied. In the first pharmacogenetic approach, genotype-phenotype associations between functional polymorphisms in $\It{CYP2D6}$ and $\It{OPRM1}$ and nausea/vomiting risk of tramadol treatment were examined. A major pathway of tramadol metabolism is demethylation to $\It{O}$-desmethyltramadol by cytochrome P450 enzyme 2D6 (CYP2D6), and $\It{O}$-desmethyltramadol has an orders-of-magnitude higher affinity for the $\mu$-opioid receptor (OPRM1) than tramadol and other metabolites. Among Ultracet? (a tablet of 37.5-mg tramadol/325-mg acetaminophen) treated 250 unrelated Korean patients with knee osteoarthritis, 54 patients having suffered from nausea and/or vomiting were compared in this study with 106 having not suffered any AE. Of 160 subjects genotyped, 154 (96.3%) were assigned $\It{CYP2D6}$alleles and were classified into two groups, extensive metabolizers (EM) and intermediate metabolizers (IM). IM subjects had 3.4-fold lower odds of nausea/vomiting than EM subjects ($\It{p}$= 0.0051). Because plasma concentration of $\It{O}$-desmethyltramadol is correlated with CYP2D6 activity level, the risk of nausea/vomiting could be attributed to $\It{O}$-desmethyltramadol. The minor-allele homozygote G/G of $\It{OPRM1}$ A118G polymorphism (rs1799971) had 6.3-fold lower odds than the major-allele homozygote A/A ($\It{p}$= 0.024). Because the A-to-G substitution substantially reduces OPRM1 mRNA and protein levels in human brain, high risk of nausea/vomiting is presumably associated with high levels of $\mu$-opioid receptor. These results suggest that $\It{O}$-desmethyltramadol binding to $\mu$-opioid receptor on the chemoreceptor trigger zone ...
Kang, Chang-Wonresearcher강창원researcher
한국과학기술원 : 생명과학과,
Issue Date
455358/325007  / 020047943

학위논문(박사) - 한국과학기술원 : 생명과학과, 2010.08, [ x, 87 p. ]


Adverse events; SNP; Pharamcogenetics; Drug response; 약물 반응성; 약물 부작용; 단일염기다형성; 약물유전학

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