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

KEYWORDS::

• children
• morphine
• OCT1
• pediatrics
• pharmacogenetics
• pharmacokinetics
• population pharmacokinetics
• surgical pain

Acknowledgements

The authors would like to thank U Christians and C Clavijo at University of Colorado (CO, USA) for their help with measuring morphine and morphine metabolite concentrations.

Financial & competing interests disclosure

This research study was supported by Children‘s Hospital Research Foundation‘s, Translational Research Award and the Outcomes Research Award, Children‘s Hospital Medical Center (OH, USA). AA Vinks was in part supported by NIH grant, 1K24HD050387. T Mizuno is supported by the Japanese Research Foundation for Clinical Pharmacology. This work was supported in part by USPHS Grant #UL1 RR026314 from the National Center for Research Resources, NIH and with the Place Outcomes Research Award and Translational Research Award, Cincinnati Children‘s Hospital Medical Center (OH, USA). Additional research funding support was provided by the Department of Anesthesia, Cincinnati Children‘s Hospital Medical Center, Cincinnati, OH, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This research study was supported by Children‘s Hospital Research Foundation‘s, Translational Research Award and the Outcomes Research Award, Children‘s Hospital Medical Center (OH, USA). AA Vinks was in part supported by National Institute of Health NIH grant, 1K24HD050387. T Mizuno is supported by the Japanese Research Foundation for Clinical Pharmacology. This work was supported in part by United States Public Health Service USPHS Grant #UL1 RR026314 from the National Center for Research Resources, NIH and with the Place Outcomes Research Award and Translational Research Award, Cincinnati Children‘s Hospital Medical Center (OH, USA). Additional research funding support was provided by the Department of Anesthesia, Cincinnati Children‘s Hospital Medical Center, Cincinnati, OH, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.