title: Methadone metabolism by early gestational age placentas.
abstract: The objective of this study was to identify the enzyme that metabolizes methadone in preterm placentas. Microsomal fractions were obtained from preterm (17 to 34 weeks) placentas (36 total; 12 per each gestational age group) and their activity in metabolizing methadone to 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) was determined. The enzyme catalyzing the reaction was identified by using chemical inhibitors selective for various cytochrome P450 isozymes and monoclonal antibodies raised against them. The metabolism of methadone by microsomes revealed saturation kinetics. Methadone was N-demethylated to EDDP by aromatase. The affinity of methadone to aromatase (apparent Km) did not change with gestation, but the activity of the enzyme (Vmax) increased and varied widely between individual placentas. Aromatase/CYP19 is the placental enzyme metabolizing methadone during pregnancy. The variability in enzyme activity among individuals should be reflected by the concentration of methadone in the fetal circulation and might be one of the factors affecting the incidence and intensity of neonatal abstinence syndrome.
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Todd Lewis
authors.initials: TL
authors.lastname: Hieronymus
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Nanovskaya
authors.forename: Sujal V
authors.initials: SV
authors.lastname: Deshmukh
authors.forename: Ricardo
authors.initials: R
authors.lastname: Vargas
authors.forename: Gary D V
authors.initials: GD
authors.lastname: Hankins
authors.forename: Mahmoud S
authors.initials: MS
authors.lastname: Ahmed
mesh_terms: D001141:Aromatase / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D006801:Humans; D066298:In Vitro Techniques; D008691:Methadone / Q000493:pharmacokinetics*; D008861:Microsomes / Q000378:metabolism; D009294:Narcotics / Q000493:pharmacokinetics*; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D011759:Pyrrolidines / Q000378:metabolism
chemical_list: D009294:Narcotics; D011759:Pyrrolidines; D001141:Aromatase; D008691:Methadone; C010724:2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine