ABCC3 and OCT1 genotypes influence pharmacokinetics of morphine in children.

ABSTRACT:

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 (∼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.

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.

SUBMITTER: Venkatasubramanian R 

PROVIDER: S-EPMC4190075 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature