Toward precision prescribing for methadone: Determinants of methadone deposition

Abstract

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.

Methadone pharmacogenetics in vitro and in vivo: Metabolism by CYP2B6 polymorphic variants and genetic variability in paediatric disposition

“…The lowest methadone clearance was observed in a CYP2B6*18 carrier, and R‐ and S‐EDDP formation clearance appeared numerically but not statistically lower in CYP2B6*6 carriers. These observations are consistent with previous observation that both CYP2B6*6 and CYP2B6*18 alleles conferred diminished methadone clearance 21,52 . For example, intravenous S‐methadone clearance in CYP2B6*1/*6 and CYP2B6*6/*6 subjects (1.2 ± 0.4 and 0.96 ± 0.33 mL/kg/min, respectively) was significantly less than in CYP2B6*1 homozygotes (1.5 ± 0.3) 21 .…”

Pharmacogenetics of lethal opioid overdose: Study protocol and preliminary findings

“…The global minor allele of the *4-allele frequency has been reported to be 29% (www.ensembl.org). CYP2B6*4 is an increased function allele, and it has been reported to increase R-and S-methadone oral clearance after a single dose intake of oral methadone in healthy volunteers [7].…”

“…Our second aim is to investigate variants in pharmacokinetic genes related to opioid transport. The P-glycoprotein protein pump, encoded by the ABCB1 gene, regulates the concentration of certain opioids (e.g., fentanyl) in the brain [7]. However, genetic variants in the ABCB1 gene have inconsistently been shown to in uence plasma levels and response of opioids in previous studies (see Table 1).…”

“…CYP3A4 poor metabolizers are rare [4], and only a small number of SNPs were found to be common in at least one of these populations: Europeans, Africans, East Asians, and Admixed Americans [5]. In contrast, variations in the CYP2B6 genes have been extensively shown to alter methadone's metabolism, plasma levels, and toxicity [6,7]. Clinical studies have indicated that CYP2B6 slow metabolizers (*6/*6 genotype) show greater (S)-methadone plasma concentration and greater risk for QT prolongation and cardiac arrhythmias, compared with normal metabolizers (*1/*10) [8,9].…”

CYP2B6 Functional Variability in Drug Metabolism and Exposure Across Populations—Implication for Drug Safety, Dosing, and Individualized Therapy

“…CYP2B6 genotype influences the plasma levels of both enantiomers (Victorri-Vigneau et al, 2019 ). Also, decreased clearance and high plasma concentration of methadone enantiomers was observed in patients with CYP2B6 * 1/ * 6 and CYP2B6 * 6/ * 6 compared to controls (Eap et al, 2007 ; Kharasch et al, 2015 ; Kringen et al, 2017 ; Talal et al, 2020 ). In a study involving 125 methadone fatality cases, the frequency of CYP2B6 * 9 was high in the methadone group compared to the control groups.…”