TY - JOUR
T1 - Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers
AU - Sistonen, J.
AU - Madadi, P.
AU - Ross, C. J.
AU - Yazdanpanah, M.
AU - Lee, J. W.
AU - Landsmeer, M. L.A.
AU - Nauta, M.
AU - Carleton, B. C.
AU - Koren, G.
AU - Hayden, M. R.
PY - 2012/4
Y1 - 2012/4
N2 - Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P trend = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P trend = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.
AB - Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P trend = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P trend = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.
UR - http://www.scopus.com/inward/record.url?scp=84862791673&partnerID=8YFLogxK
U2 - 10.1038/clpt.2011.280
DO - 10.1038/clpt.2011.280
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C2 - 22398969
AN - SCOPUS:84862791673
SN - 0009-9236
VL - 91
SP - 692
EP - 699
JO - Clinical Pharmacology and Therapeutics
JF - Clinical Pharmacology and Therapeutics
IS - 4
ER -