title: ABCB1 c.2677G>T variation is associated with adverse reactions of OROS-methylphenidate in children and adolescents with ADHD.
abstract: OBJECTIVE
  Osmotic-release oral system (OROS)-methylphenidate (MPH) is a safe and well-tolerated drug. Some patients cannot continue this regimen with adverse drug reactions (ADRs). As drug efflux transporters of the central nervous system, ABCB1 plays an important role in the clearance of psychotropic drugs and their metabolites from brain tissues. We hypothesized that genetic variations in the ABCB1 gene may affect ADRs to OROS-MPH.
  
  
  METHODS
  We analyzed ADRs of OROS-MPH in 134 children and adolescents with attention-deficit hyperactivity disorder who completed a 4-week trial of OROS-MPH. The ADRs of OROS-MPH were evaluated by administering the Barkley Stimulant Side Effects Rating Scale.
  
  
  RESULTS
  Our study proved that MPH is a substrate for ABCB1 by using membrane vesicle assay. We analyzed the influence of ABCB1 polymorphisms on ADRs to OROS-MPH. From the association study between ABCB1 polymorphisms and ADRs of OROS-MPH, c.2677G>T (p.Ala893Ser, rs2032582) showed a strong association with OROS-MPH-related ADRs (P = 0.008; odds ratio, 5.72). Furthermore, logistic regression analysis indicated that the TT genotype at the ABCB1 2677 locus is an independent determinant of ADRs attributed to OROS-MPH. In a functional study, the 893Ser variant markedly reduced MPH transport across the cell membrane.
  
  
  CONCLUSIONS
  This is the first study to demonstrate that the TT genotype at position 2677 in the ABCB1 gene is associated with ADRs to OROS-MPH.
authors.affiliation: Department of Pharmacology, Pharmacogenomic Research Center for Membrane Transporters, Brain Korea 21 Project for Medical Science, Seoul, Korea.
authors.forename: So Won
authors.initials: SW
authors.lastname: Kim
authors.forename: Ji Hyun
authors.initials: JH
authors.lastname: Lee
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Hong
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Ki-Hwan
authors.initials: KH
authors.lastname: Yook
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000367:Age Factors; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D000697:Central Nervous System Stimulants / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D016009:Chi-Square Distribution; D002648:Child; D016503:Drug Delivery Systems; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D016015:Logistic Models; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism; D016017:Odds Ratio; D009995:Osmosis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D012307:Risk Factors; D014162:Transfection; D016896:Treatment Outcome
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000697:Central Nervous System Stimulants; D008774:Methylphenidate