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.

Analgesia and Opioids: A Pharmacogenetics Shortlist for Implementation in Clinical Practice

“…Studies assessing whether these findings apply to pain phenotypes in different pediatric age ranges are needed, as well as studies on the clinical consequence of SLC22A1 genetic variability in the pediatric population. Sufficient evidence on tramadol and morphine PK with SLC22A1 genetics has been found in adult and pediatric populations, with all studies replicating and confirming previous findings (39,42,44,47 ).…”

“…In a study with 103 adult white individuals, 51 genetic variations were discovered, but only the promoter SNP Ϫ211CϾT (rs4793665) was associated with significantly decreased ABCC3 mRNA expression and alterations in the binding of transcription factors (38 ). A study with 105 children undergoing adenotonsillectomy indicated that the Ϫ211CϾT polymorphism was associated with lower M3G and M6G plasma concentrations (39 ). All 12 patients with undetectable M6G concentrations were carriers of the T-allele, which is in line with in vitro data from Lang et al (38 ).…”

“…The association of these deficient SLC22A1 alleles with morphine was confirmed in a pediatric cohort with 220 children aged 6 -15 years. The children with 2 loss-offunction alleles treated with intravenous morphine for postoperative pain had significantly lower clearance compared with patients with wild-type alleles (39 ). The authors proposed that these genetic variants could explain why children with a white background experienced more adverse events than African American children, in whom the variant alleles are less frequent.…”

OCT1 Genetic Variants are Associated with Postoperative Morphine-Related Adverse Effects in Children

“…We earlier studied formation of morphine metabolites, morphine-6-glucuronide and morphine-3-glucuronide along with morphine clearance [11]. The OCT1 homozygotes had lower morphine clearance and reduced metabolite formation (∼39%).…”

“…The efflux of morphine glucuronides from the hepatic cell is an ATP-dependent process mediated by the ATP-binding cassette transporters including ABCC3 [9,10]. We recently demonstrated that ABCC3 variants contribute to variability in morphine, morphine-3-glucuronide and morphine-6-glucuronide pharmacokinetics (PK) and clinical outcomes [11,12].…”