title: ABCC3 and OCT1 genotypes influence pharmacokinetics of morphine in children.
abstract: OBJECTIVE
  Large interindividual variability in morphine pharmacokinetics could contribute to variability in morphine analgesia and adverse events.
  
  
  METHODS
  Influence of weight, genetic polymorphisms, race and sex on morphine clearance and metabolite formation from 220 children undergoing outpatient adenotonsillectomy was studied. A nonlinear mixed effects model was developed in NONMEM to describe morphine and morphine glucuronide pharmacokinetics.
  
  
  RESULTS
  Children with ABCC3 -211C>T polymorphism C/C genotype had significantly higher levels of morphine-6-glucuronide and morphine-3-glucuronide formation (∼40%) than C/T+T/T genotypes (p < 0.05). In this extended cohort similar to our earlier report, OCT1 homozygous genotypes (n = 13, OCT1*2-*5/*2-*5) had lower morphine clearance (14%; p = 0.06), and in addition complementing lower metabolite formation (∼39%) was observed. ABCB1 3435C>T TT genotype children had lower levels of morphine-3-glucuronide formation though no effect was observed on morphine and morphine-6-glucuronide pharmacokinetics.
  
  
  CONCLUSIONS
  Our data suggest that besides bodyweight, OCT1 and ABCC3 genotypes play a significant role in the pharmacokinetics of intravenous morphine and its metabolites in children.
authors.affiliation: Department of Anesthesia, Cincinnati Children's Hospital Medical Center; 3333 Burnet Avenue, MLC 2001, Cincinnati, OH 45229, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Venkatasubramanian
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Jing
authors.initials: J
authors.lastname: Niu
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mizuno
authors.forename: Vidya
authors.initials: V
authors.lastname: Chidambaran
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Vinks
authors.forename: Senthilkumar
authors.initials: S
authors.lastname: Sadhasivam
mesh_terms: D000293:Adolescent; D002648:Child; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D027702:Organic Cation Transporter 1 / Q000235:genetics*; D010149:Postoperative Pain / Q000188:drug therapy* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014068:Tonsillectomy; D044465:White People
chemical_list: D009020:Morphine; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027702:Organic Cation Transporter 1; C114462:multidrug resistance-associated protein 3
keywords: ABCB1; ABCC3; OCT1; morphine; pediatrics; pharmacogenetics; population pharmacokinetics; surgical pain