ABCC3 and OCT1 genotypes influence pharmacokinetics of morphine in children

Aim: 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 (similar to 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(star)2-(star)5/(star)2-(star)5) had lower morphine clearance (14%; p = 0.06), and in addition complementing lower metabolite formation (similar to 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. Conclusion: 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.