TY - JOUR
KW - Alleles
KW - Analgesics, Opioid/therapeutic use
KW - Cross-Sectional Studies
KW - Cytochrome P-450 CYP2B6/genetics
KW - Cytochrome P-450 CYP3A/genetics
KW - Ethnic Groups
KW - Female
KW - Genotype
KW - Humans
KW - Male
KW - Methadone/therapeutic use
KW - Middle Aged
KW - Minority Groups
KW - Opioid-Related Disorders/drug therapy
KW - Point-of-Care Systems
KW - Polymorphism, Genetic/genetics
KW - Precision Medicine
AU - A. H. Talal
AU - Y. Ding
AU - C. S. Venuto
AU - L. M. Chakan
AU - A. McLeod
AU - A. Dharia
AU - G. D. Morse
AU - L. S. Brown
AU - M. Markatou
AU - E. D. Kharasch
A1 - 
AB - BACKGROUND: Despite the World Health Organization listing methadone as an essential medication, effective dose selection is challenging, especially in racial and ethnic minority populations. Subtherapeutic doses can result in withdrawal symptoms while supratherapeutic doses can result in overdose and death. Although CYP3A4 was conventionally considered the principal methadone metabolizing enzyme, more recent data have identified CYP2B6 as the principal enzyme. CYP2B6 has ethnically-associated polymorphisms that affect the metabolic rate. Our objective was to investigate the effects of genetic and nongenetic factors on methadone metabolism. METHODS: We measured trough plasma methadone levels in 100 participants with opioid use disorder. We assessed methadone metabolism by calculating the metabolite ratio (major metabolite: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine [EDDP] divided by methadone concentration). We assessed hepatic fibrosis and steatosis by transient elastography and CYP2B6 alleles, principally responsible for methadone metabolism. Mixed effects models modeled the data in 97 participants. RESULTS: Participants were largely male (58%), minority (61% African American) and non-Hispanic (68%). Forty percent were HCV mono-infected, 40% were uninfected, and 20% were HCV/HIV co-infected. Female sex had significant effects on (R)- and (S)-methadone metabolism (p = 0.016 and p = 0.044, respectively). CYP2B6 loss of function (LOF) alleles significantly affected (S)-methadone metabolism (p = 0.012). Body mass index (BMI) significantly affected (R)-methadone metabolism (p = 0.034). Methadone metabolism appeared to be lower in males, in individuals with LOF alleles, and elevated BMI. CONCLUSIONS: Genetic analysis, especially in minority populations, is essential to delivering individualized treatments. Although the principal methadone metabolizing enzyme remains controversial, our results suggest that sex, CYP2B6 genotype, and BMI should be incorporated into multivariate models to create methadone dosing algorithms. Methadone dosing algorithms should facilitate medication delivery, improve patient satisfaction, and diminish overdose potential.
AD - Division of Gastroenterology, Hepatology and Nutrition, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States of America.; Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, United States of America.; Department of Neurology, University of Rochester, Rochester, NY, United States of America.; Division of Gastroenterology, Hepatology and Nutrition, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States of America.; START Treatment & Recovery Centers, Brooklyn, NY, United States of America.; Division of Gastroenterology, Hepatology and Nutrition, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States of America.; NYS Center of Excellence in Bioinformatics and Life Sciences, University at Buffalo, Buffalo, NY, United States of America.; START Treatment & Recovery Centers, Brooklyn, NY, United States of America.; Department of Biostatistics, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY, United States of America.; Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States of America.
BT - PloS one
C5 - Education & Workforce; Healthcare Disparities; Opioids & Substance Use
CP - 4
DO - 10.1371/journal.pone.0231467
IS - 4
JF - PloS one
LA - eng
M1 - Journal Article
N2 - BACKGROUND: Despite the World Health Organization listing methadone as an essential medication, effective dose selection is challenging, especially in racial and ethnic minority populations. Subtherapeutic doses can result in withdrawal symptoms while supratherapeutic doses can result in overdose and death. Although CYP3A4 was conventionally considered the principal methadone metabolizing enzyme, more recent data have identified CYP2B6 as the principal enzyme. CYP2B6 has ethnically-associated polymorphisms that affect the metabolic rate. Our objective was to investigate the effects of genetic and nongenetic factors on methadone metabolism. METHODS: We measured trough plasma methadone levels in 100 participants with opioid use disorder. We assessed methadone metabolism by calculating the metabolite ratio (major metabolite: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine [EDDP] divided by methadone concentration). We assessed hepatic fibrosis and steatosis by transient elastography and CYP2B6 alleles, principally responsible for methadone metabolism. Mixed effects models modeled the data in 97 participants. RESULTS: Participants were largely male (58%), minority (61% African American) and non-Hispanic (68%). Forty percent were HCV mono-infected, 40% were uninfected, and 20% were HCV/HIV co-infected. Female sex had significant effects on (R)- and (S)-methadone metabolism (p = 0.016 and p = 0.044, respectively). CYP2B6 loss of function (LOF) alleles significantly affected (S)-methadone metabolism (p = 0.012). Body mass index (BMI) significantly affected (R)-methadone metabolism (p = 0.034). Methadone metabolism appeared to be lower in males, in individuals with LOF alleles, and elevated BMI. CONCLUSIONS: Genetic analysis, especially in minority populations, is essential to delivering individualized treatments. Although the principal methadone metabolizing enzyme remains controversial, our results suggest that sex, CYP2B6 genotype, and BMI should be incorporated into multivariate models to create methadone dosing algorithms. Methadone dosing algorithms should facilitate medication delivery, improve patient satisfaction, and diminish overdose potential.
PY - 2020
SN - 1932-6203; 1932-6203
T1 - Toward precision prescribing for methadone: Determinants of methadone deposition
T2 - PloS one
TI - Toward precision prescribing for methadone: Determinants of methadone deposition
U1 - Education & Workforce; Healthcare Disparities; Opioids & Substance Use
U2 - 32302325
U3 - 10.1371/journal.pone.0231467
VL - 15
VO - 1932-6203; 1932-6203
Y1 - 2020
Y2 - Apr 17
ER -