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Research ArticleArticle

The Impact of Age and Genetics on Naltrexone Biotransformation

Stephani L. Stancil, Whitney Nolte, Robin E. Pearce, Vincent S. Staggs and J. Steven Leeder
Drug Metabolism and Disposition February 2022, 50 (2) 168-173; DOI: https://doi.org/10.1124/dmd.121.000646
Stephani L. Stancil
Division of Adolescent Medicine (S.L.S.), Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (S.L.S., W.N., R.E.P., J.S.L.), and Biostatistics and Epidemiology Core (V.S.S.) Children’s Mercy Kansas City, Kansas City, Missouri; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri (S.L.S., W.N., R.E.P., V.S.S., J.S.L.)
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Whitney Nolte
Division of Adolescent Medicine (S.L.S.), Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (S.L.S., W.N., R.E.P., J.S.L.), and Biostatistics and Epidemiology Core (V.S.S.) Children’s Mercy Kansas City, Kansas City, Missouri; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri (S.L.S., W.N., R.E.P., V.S.S., J.S.L.)
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Robin E. Pearce
Division of Adolescent Medicine (S.L.S.), Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (S.L.S., W.N., R.E.P., J.S.L.), and Biostatistics and Epidemiology Core (V.S.S.) Children’s Mercy Kansas City, Kansas City, Missouri; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri (S.L.S., W.N., R.E.P., V.S.S., J.S.L.)
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Vincent S. Staggs
Division of Adolescent Medicine (S.L.S.), Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (S.L.S., W.N., R.E.P., J.S.L.), and Biostatistics and Epidemiology Core (V.S.S.) Children’s Mercy Kansas City, Kansas City, Missouri; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri (S.L.S., W.N., R.E.P., V.S.S., J.S.L.)
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J. Steven Leeder
Division of Adolescent Medicine (S.L.S.), Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation (S.L.S., W.N., R.E.P., J.S.L.), and Biostatistics and Epidemiology Core (V.S.S.) Children’s Mercy Kansas City, Kansas City, Missouri; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri (S.L.S., W.N., R.E.P., V.S.S., J.S.L.)
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Abstract

Naltrexone, an opioid antagonist primarily metabolized by aldo-keto reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n = 158) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of naltrexone (0.1, 1 µM). Naltrexone biotransformation was determined by ultraperformance mass spectrometry quantification of the primary metabolite, 6-beta-naltrexol (6βN), and 6βN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0–79 y (mean 16.0 ± 18.2 y), 37% (n = 60) female, 20% (n = 33) heterozygous and 1.2% (n = 2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6βN formation (0.37–76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0–18 y) suggested that AKR1C4 genetic variation, age, and sex explained 36% of the variability in 6βN formation. Although activity increased steadily from birth and peaked in middle childhood (2–5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. Naltrexone biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study Naltrexone responsiveness in children and adults.

SIGNIFICANCE STATEMENT Biotransformation of the commonly used opioid antagonist naltrexone is highly variable and may contribute to reduced therapeutic response. Age, sex, and genetic variation in the drug-metabolizing enzyme, AKR1C4, are potential factors contributing to this variability. In pediatric samples, genetic variation (S145C/L311V) demonstrates a greater impact on activity than age. Additionally, the source of donor samples was identified as an important contributor and must be accounted for to confidently elucidate the biological variables most impactful to drug biotransformation.

Footnotes

    • Received August 24, 2021.
    • Accepted November 1, 2021.
  • This work was supported by grants T32 HD069038 (S.L.S.) and U54 HD090258 (J.S.L.) from the Eunice Kennedy Shriver National Institute of Child Health and Development.

  • The authors declare that they have no conflicts of interest with the contents of the article.

  • https://dx.doi.org/10.1124/dmd.121.000646.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 50 (2)
Drug Metabolism and Disposition
Vol. 50, Issue 2
1 Feb 2022
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Research ArticleArticle

Variability in Naltrexone Biotransformation

Stephani L. Stancil, Whitney Nolte, Robin E. Pearce, Vincent S. Staggs and J. Steven Leeder
Drug Metabolism and Disposition February 1, 2022, 50 (2) 168-173; DOI: https://doi.org/10.1124/dmd.121.000646

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Research ArticleArticle

Variability in Naltrexone Biotransformation

Stephani L. Stancil, Whitney Nolte, Robin E. Pearce, Vincent S. Staggs and J. Steven Leeder
Drug Metabolism and Disposition February 1, 2022, 50 (2) 168-173; DOI: https://doi.org/10.1124/dmd.121.000646
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