Effects of genotype and food on naltrexone exposure in adolescents
Abstract Naltrexone (NTX), an opioid antagonist metabolized by aldo‐keto reductase 1C4 (AKR1C4), is prescribed for psychiatric conditions like eating disorders with variable response. Systemic exposure is highly variable in adults, yet no data exist in children. The purpose of this study was to eval...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-11-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13399 |
| _version_ | 1811180306492817408 |
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| author | Stephani L. Stancil Michaela Voss Whitney Nolte John Tumberger William Adelman Susan Abdel‐Rahman |
| author_facet | Stephani L. Stancil Michaela Voss Whitney Nolte John Tumberger William Adelman Susan Abdel‐Rahman |
| author_sort | Stephani L. Stancil |
| collection | DOAJ |
| description | Abstract Naltrexone (NTX), an opioid antagonist metabolized by aldo‐keto reductase 1C4 (AKR1C4), is prescribed for psychiatric conditions like eating disorders with variable response. Systemic exposure is highly variable in adults, yet no data exist in children. The purpose of this study was to evaluate NTX exposure in adolescents with eating disorders. Adolescents aged 12–21 years with eating disorders underwent postdose blood sampling in the fasted and/or fed state. NTX and primary active metabolite, 6‐β‐naltrexol, were determined by ultra‐high performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. DNA was genotyped for AKR1C4 missense mutations associated with decreased activity (rs3829125 and rs17134592). Linear mixed effects modeling was performed. In 21 participants, aged 16.9 ± 1.9 years (15–21 years), 81% female participants, maximum concentration (Cmax) was 90.4 ± 129 nM/mg/kg, area under the concentration‐time curve from zero to infinity (AUC0–∞) was 166 ± 154 nM h/mg/kg, and varied 63‐fold and 21‐fold, respectively. Compared with wildtype, those with AKR1C4 allelic variations (n = 7) displayed 3.2‐fold higher AUC0–∞, four‐fold higher Cmax and delayed time to Tmax. Linear mixed effects modeling demonstrated a large effect of genotype on AUC0–∞ (Cohen's d −2.3) and Cmax (Cohen's d −1.4). Food effect was large for AUC0–∞ (Cohen's d 2.6), but highly variable and failed to reach significance for Cmax. The respective model accounted for 82% of the variance in NTX AUC0–∞ and 46% of the variance in Cmax. NTX systemic exposure is highly variable in adolescents with eating disorders and modulated, in part, by AKR1C4 genotype and food intake. These findings may, in part, explain the large degree of interindividual variability observed response to NTX. |
| first_indexed | 2024-04-11T06:48:07Z |
| format | Article |
| id | doaj.art-906c06ea3dd049d8b0c7293218ba78b2 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-11T06:48:07Z |
| publishDate | 2022-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-906c06ea3dd049d8b0c7293218ba78b22022-12-22T04:39:17ZengWileyClinical and Translational Science1752-80541752-80622022-11-0115112732274310.1111/cts.13399Effects of genotype and food on naltrexone exposure in adolescentsStephani L. Stancil0Michaela Voss1Whitney Nolte2John Tumberger3William Adelman4Susan Abdel‐Rahman5Division of Adolescent Medicine Children's Mercy Hospital – Kansas City Kansas City Missouri USADivision of Adolescent Medicine Children's Mercy Hospital – Kansas City Kansas City Missouri USADivision of Clinical Pharmacology, Toxicology and Therapeutic Innovation Children's Mercy Hospital – Kansas City Kansas City Missouri USADivision of Adolescent Medicine Children's Mercy Hospital – Kansas City Kansas City Missouri USADepartment of Student Health and Counseling, Division of Wellness The University of Pennsylvania Philadelphia Pennsylvania USADivision of Clinical Pharmacology, Toxicology and Therapeutic Innovation Children's Mercy Hospital – Kansas City Kansas City Missouri USAAbstract Naltrexone (NTX), an opioid antagonist metabolized by aldo‐keto reductase 1C4 (AKR1C4), is prescribed for psychiatric conditions like eating disorders with variable response. Systemic exposure is highly variable in adults, yet no data exist in children. The purpose of this study was to evaluate NTX exposure in adolescents with eating disorders. Adolescents aged 12–21 years with eating disorders underwent postdose blood sampling in the fasted and/or fed state. NTX and primary active metabolite, 6‐β‐naltrexol, were determined by ultra‐high performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. DNA was genotyped for AKR1C4 missense mutations associated with decreased activity (rs3829125 and rs17134592). Linear mixed effects modeling was performed. In 21 participants, aged 16.9 ± 1.9 years (15–21 years), 81% female participants, maximum concentration (Cmax) was 90.4 ± 129 nM/mg/kg, area under the concentration‐time curve from zero to infinity (AUC0–∞) was 166 ± 154 nM h/mg/kg, and varied 63‐fold and 21‐fold, respectively. Compared with wildtype, those with AKR1C4 allelic variations (n = 7) displayed 3.2‐fold higher AUC0–∞, four‐fold higher Cmax and delayed time to Tmax. Linear mixed effects modeling demonstrated a large effect of genotype on AUC0–∞ (Cohen's d −2.3) and Cmax (Cohen's d −1.4). Food effect was large for AUC0–∞ (Cohen's d 2.6), but highly variable and failed to reach significance for Cmax. The respective model accounted for 82% of the variance in NTX AUC0–∞ and 46% of the variance in Cmax. NTX systemic exposure is highly variable in adolescents with eating disorders and modulated, in part, by AKR1C4 genotype and food intake. These findings may, in part, explain the large degree of interindividual variability observed response to NTX.https://doi.org/10.1111/cts.13399 |
| spellingShingle | Stephani L. Stancil Michaela Voss Whitney Nolte John Tumberger William Adelman Susan Abdel‐Rahman Effects of genotype and food on naltrexone exposure in adolescents Clinical and Translational Science |
| title | Effects of genotype and food on naltrexone exposure in adolescents |
| title_full | Effects of genotype and food on naltrexone exposure in adolescents |
| title_fullStr | Effects of genotype and food on naltrexone exposure in adolescents |
| title_full_unstemmed | Effects of genotype and food on naltrexone exposure in adolescents |
| title_short | Effects of genotype and food on naltrexone exposure in adolescents |
| title_sort | effects of genotype and food on naltrexone exposure in adolescents |
| url | https://doi.org/10.1111/cts.13399 |
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