Abstract

Naltrexone (NTX), 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=163) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of NTX (0.1, 1 µM). NTX biotransformation was determined by UPLC-MS/MS 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{plus minus}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 0-18y) 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. NTX 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 NTX 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.