Edifenphos (EDDP) [BGG]

To examine the effect of a single oral dose of methadone on cytochrome P450 (CYP) 3A activity using the urinary 6 beta -hydroxycortisol to cortisol ratio (UCR) as a marker of CYP3A activity. Methods A single oral dose (0.2 mg kg(-1)) of rac-methadone was administered to eight healthy female volunteers. Frequent blood samples and all urine over seven time periods was collected For 96 h following dosing. The UCR and the concentration of the major CYP3A metabolite of methadone, EDDP, were measured in urine. Methadone enantiomer concentrations were determined in plasma and urine. All quantifications were performed by validated high performance liquid chromatography assays. Results In all Volunteers a significant decline of the UCR from immediately predose values was observed at the 4-8 and 8-12 h collection periods (P < 0.05, 95% CI for the differences. 0.4.16 and 0.6.16, respectively) with a return to immediately predose values after 2-3 days, suggesting methadone was an inhibitor of CYP3A. The UCR was found to be significantly correlated with the amount of EDDP excreted in the urine and with the area under the plasma concentration vs time profile for total (R + S) methadone supporting in vitro data that CYP3A is primarily responsible for EDDP formation and has a significant influence on methadone disposition. Conclusions Methadone appears to be a CYP3A inhibitor in vivo following a single oral dose and measurements of the urinary cortisol ratio appear to be a useful index to follow this inhibition.

Background: Severe neonatal opioid withdrawal syndrome (NOWS) cannot be predicted. Placental aromatase metabolizes both methadone and buprenorphine and may contribute to the severity of NOWS.Objectives: To determine whether placental aromatase mRNA expression differs in methadone- or buprenorphine-exposed placentas and is associated with NOWS severity.Study design: Prospective multicenter observational cohort study from July 2016 to December 2017. Inclusion: pregnant, 18years old, singleton fetus, nonanomalous, 34weeks at delivery, documented methadone or buprenorphine use. Exclusion: declined sample collection. Severe NOWS is defined as three consecutive Finnegan scores 8 or sum of three consecutive scores 24 within 72hours of birth. Finnegan scoring was correlated with placental mRNA expression and compared to umbilical cord drug and metabolite levels. Data were analyzed using descriptive, parametric, and nonparametric statistics and regression analysis. p-Value <.05 was considered significant.Results: Thirty-eight out of 45 (84%) patients were included. Methadone and buprenorphine were used by 29/38 (76%) and 9/38 (24%) of patients, respectively. 19/38 (50%) infants had severe NOWS. Placental aromatase/actin mRNA expression was significantly lower in the placentas of infants with severe NOWS (p = .04). Mean umbilical cord 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)/methadone ratios were significantly higher in infants with severe NOWS (p = .03). Placental aromatase mRNA expression was weakly to moderately correlated with umbilical cord methadone, buprenorphine, and their metabolite concentrations (r=0.4-0.8).Conclusion: Placental aromatase mRNA expression was lower and umbilical cord EDDP/methadone ratios were higher in infants with severe NOWS. Additional investigation of placental aromatase in methadone- and buprenorphine-exposed pregnancies is needed.