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.

Keywords: ABCB1; ABCC3; OCT1; morphine; pediatrics; pharmacogenetics; population pharmacokinetics; surgical pain.

Figures

Figure 1. Hepatocyte uptake, metabolism, biliary efflux and efflux into plasma of morphine and its two prominent metabolites, morphine-3-glucuronide and morphine-6-glucuronide

Morphine is metabolized to M3G and M6G by UGT1A1 and UGT2B7 [43-45]. Morphine has been demonstrated to be an OCT1 substrate though the role of OCT1 in the uptake of M3G/M6G has not been reported [11]. ABCC3 is known to transport morphine glucuronides back into plasma while morphine has not been reported to be its substrate [14]. ABCB1, primarily expressed on the canalicular side is known to transport morphine and M6G, though M3G has been reported to not be a substrate [8-10,13]. ABCC2, expressed on the canalicular side, transports morphine glucuronides in mice into bile [7,12], while morphine is not known to be substrate. M3G: Morphine-3-glucuronide; M6G: Morphine-6-glucuronide.

Figure 2. Pharmacokinetic model for morphine, morphine-3-glucuronide and morphine-6-glucuronide

Morphine pharmacokinetics were characterized using two compartments (parameterized using CL, V1, Q and V2). The delay in the formation of metabolites was modeled using a hypothetical delay compartment. Mass transfer between the central compartment and the delay compartment was modeled using a single rate constant (ke0). The metabolite concentrations were modeled using one compartment each, with metabolite formation and clearance modeled using FCL (FCLM3G and FCLM3G), V (VM3G and VM6G) and CL (CLM3G and CLM6G). CL: Clearance; FCL: Formation clearance; M3G: Morphine-3-glucuronide; M6G: Morphine-6-glucuronide; Q: Intercompartmental clearance; V: Volume of distribution.

Figure 3. Plasma concentration–time profiles for morphine, morphine-3-glucuronide and morphine-6-glucuronide observed in the current study cohort

All plots are in the semi-log scale and concentrations are in ng/ml. Conc: Concentration; M3G: Morphine-3-glucuronide; M6G: Morphine-6-glucuronide.

Figure 4. Variation of weight normalized morphine clearance and morphine-3-glucuronide and morphine-6-glucuronide formation clearances with OCT1, ABCC3 and ABCB1 genotype observed in our study

OCT1 genotype has been divided into three groups (defined in Table 1). CL: Clearance; HM: Homozygous; HT: Heterozygous; M3G: Morphine-3-glucuronide; M6G: Morphine-6-glucuronide; WT: Wild-type.