title: Cytochrome P450 2D6 polymorphisms and predicted opioid metabolism in African American children with sickle cell disease.
abstract: The opioid medications codeine and hydrocodone, commonly prescribed in sickle cell disease (SCD), require metabolic conversion by cytochrome P450 2D6 (CYP2D6) to morphine and hydromorphone, respectively, to exert their analgesic effects. The CYP2D6 gene is highly polymorphic, with variant alleles that result in decreased, absent, or ultrarapid enzyme activity. Seventy-five children with SCD were tested for CYP2D6 polymorphisms, and metabolic phenotypes were inferred from the genotypes. The most common variant alleles were CYP2D6*2 (normal activity, 28.7%), CYP2D6*17 (reduced activity, 17.3%), CYP2D6*5 (gene deletion, 8.7%), and CYP2D6*4 (absent function, 8.0%). Normal/extensive metabolizer genotypes were found in 28/75 (37.5%), intermediate metabolism in 33/75 (44.0%), poor metabolism in 4/75 (5.3%), ultrarapid metabolism in 3/75 (4.0%), indeterminate in 6/75 (8.0%). Allele frequencies did not vary significantly among different hemoglobin genotypes. Identification of variant CYP2D6 genotypes may identify individuals with altered metabolism and therefore altered analgesic response to codeine and hydrocodone, thus providing a personalized medicine approach to treatment of pain in SCD. Further pharmacokinetic and pharmacodynamic studies are needed to define the relationship of CYP2D6 and other gene polymorphisms to individual opioid effect in SCD.
authors.affiliation: *Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta Departments of †Pediatrics, Hematology/Oncology ‡Pathology and Laboratory Medicine, Emory University §Emory University School of Medicine, Atlanta, GA.
authors.forename: Marianne M
authors.initials: MM
authors.lastname: Yee
authors.forename: Cassandra
authors.initials: C
authors.lastname: Josephson
authors.forename: Charles E
authors.initials: CE
authors.lastname: Hill
authors.forename: Rosiland
authors.initials: R
authors.lastname: Harrington
authors.forename: Marta-Inés
authors.initials: MI
authors.lastname: Castillejo
authors.forename: Ruan
authors.initials: R
authors.lastname: Ramjit
authors.forename: Ifeyinwa
authors.initials: I
authors.lastname: Osunkwo
mesh_terms: D000293:Adolescent; D001741:Black or African American / Q000235:genetics*; D000483:Alleles; D000701:Analgesics, Opioid / Q000378:metabolism*; D000755:Anemia, Sickle Cell / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D010641:Phenotype; D011110:Polymorphism, Genetic
chemical_list: D000701:Analgesics, Opioid; D019389:Cytochrome P-450 CYP2D6