OCT1 genetic variants influence the pharmacokinetics of morphine in children

Abstract

Aim: Large interindividual variability in morphine disposition could contribute to unpredictable variability in morphine analgesia and adverse events. Caucasian children have more adverse effects and slower morphine clearance than African-American children. To study variations in intravenous morphine pharmacokinetics in children, we examined the influence of genetic polymorphisms in OCT1.

Methods: In 146 children undergoing adenotonsillectomy, 146 concentration-time profiles (2-4 measurements per patient) were available. Population pharmacokinetic analysis characterized the profiles in NONMEM(®) and tested OCT1 variants as covariates.

Results: Allometrically scaled post hoc Bayesian morphine clearance in homozygotes of loss-of-function OCT1 variants (n = 9, OCT1*2-*5/*2-*5) was significantly lower (20%) than in wild-type (n = 85, OCT1*1/*1) and heterozygotes (n = 52, OCT1*1/*2-*5; p < 0.05).

Conclusion: Besides bodyweight, OCT1 genotypes play a significant role in intravenous morphine pharmacokinetics. Relatively high allelic frequencies of defective OCT1 variants among Caucasians may explain their lower morphine clearance and possibly higher frequencies of adverse events compared with African-American children. Original submitted 21 December 2012; Revision submitted 7 May 2013.

Figures

Figure 1. Hypothetical morphine transportation and biotransformation

OCT1 is localized in the sinusoidal membrane of the human hepatocyte and mediates cellular uptake of substrates into the liver. ABCC3 (mrp3 in mice) is proposed to mediate the export of morphine back to blood [28]. The main metabolic enzyme of morphine is UGT2B7. P-gp and ABCC2 may mediate export of morphine and its metabolites to bile.

Figure 2. Morphine clearance standardized to a 70-kg person versus OCT1 genotype

Variation of empirical Bayesian estimates for individual morphine clearance standardized to a 70-kg person with respect to the OCT1 genotype. Homozygotes for defective OCT1 alleles were found to have a significantly lower clearance as compared with subjects with at least one active allele.

Figure 3. Individual morphine clearances versus OCT1 genotype among five different weight groups

Variation of empirical Bayesian estimates for individual morphine clearance with respect to the OCT1 genotype stratified by weight. Homozygotes for defective OCT1 alleles consistently had significantly lower clearance as compared with subjects with at least one active allele while heterozygotes had lower clearance than the wild-type in the lowest weight groups. Circles represent individual clearance estimates from patients who were recognized as outliers or who were homozygous for the defective OCT1 variants. Numbers represent number of subjects (in each bodyweight category) with different OCT1 genotypes. CL: Clearance; Hetero: Heterozygote; Homo: Homozygote; Wild: Wild-type.