Bidirectional transfer of methadone across human placenta (original) (raw)
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Transfer of methadone across the dually perfused preterm human placental lobule
American Journal of Obstetrics and Gynecology, 2008
The objective of the study was to determine the effect of gestational age and P-glycoprotein expression on transplacental transfer of methadone. STUDY DESIGN: Dual perfusion of placental lobule was utilized. Methadone (200 ng/mL) and its [ 3 H]-isotope were cotransfused from the maternal-to-fetal circuit with the marker compound antipyrine (20 g/ mL) and its [ 14 C]-isotope. Concentration of the drugs in trophoblast tissue and both circuits was determined by liquid scintillation spectrometry.
Methadone metabolism by human placenta
Biochemical Pharmacology, 2004
Methadone pharmacotherapy is considered the standard for treatment of the pregnant heroin/opioid addict. One of the factors affecting the transfer kinetics of opioids across human placenta and their levels in the fetal circulation is their metabolism by the tissue. The aim of this investigation is to identify the enzyme(s) responsible for the metabolism of methadone, determine the kinetics of the reaction and the metabolites formed utilizing placental tissue obtained from term healthy pregnancies. Microsomal fractions of trophoblast tissue homogenates had the highest activity in catalyzing the metabolism of methadone. The product formed was identified by HPLC-UV as 2ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). Inhibitors selective for cytochrome P450 (CYP) isozymes were used to identify the enzyme catalyzing the biotransformation of methadone. Aminoglutethimide and 4-hydroxyandrostenedione inhibited EDDP formation by 88 and 70%, respectively, suggesting that CYP19/aromatase is the enzyme catalyzing the reaction. This was confirmed by the effect of monoclonal antibodies raised against CYP19 that caused an 80% inhibition of the reaction. The apparent K m and V max values for the CYP19 catalyzed metabolism of methadone to EDDP were 424 AE 92 mM and 420 AE 89 pmol (mg protein) À1 min À1 , respectively. Kinetic analysis of a cDNA-expressed CYP19 for the metabolism of methadone to EDDP was identical to that by placental microsomes. Taken together, these data indicate that CYP19/aromatase is the major enzyme responsible for the metabolism of methadone to EDDP in term human placentas obtained from healthy pregnancies.
Role of P-glycoprotein in transplacental transfer of methadone
Biochemical Pharmacology, 2005
Methadone is the therapeutic agent of choice for treatment of the pregnant opiate addict. However, little is known on the factors affecting its concentration in the fetal circulation during pregnancy and how it might relate to neonatal outcome. Therefore, a better understanding of the function of placental metabolic enzymes and transporters should add to the knowledge of the role of the tissue in the disposition of methadone and its relation to neonatal outcome. We hypothesized that the expression and activity of the placental efflux transporter P-glycoprotein (P-gp) would affect the transfer of methadone to the fetal circulation. Data obtained utilizing dual perfusion of placental lobule and monolayers of Be-Wo cell line indicated that methadone is extruded by P-gp. Transfer of methadone to the fetal circuit was increased by 30% in the presence of the P-gp inhibitor GF120918 while the transfer of paclitaxel, a typical substrate of the glycoprotein, was increased by 50%. In the Be-Wo cell line, methadone and paclitaxel uptake was also increased in the presence of the P-gp inhibitor cyclosporin A. Moreover, the expression of P-gp in placental brush-border membranes varied between term placentas. Taken together, these data strongly suggest that the concentration of methadone in the fetal circulation is affected by the expression and activity of P-gp. It is reasonable to speculate that placental disposition of methadone affects its concentration in the fetal circulation. If true, this may also be directly related to the incidence and intensity of neonatal abstinence syndrome (NAS).
The impact of cocaine and heroin on the placental transfer of methadone
Reproductive Biology and Endocrinology, 2009
Background: Methadone is the therapeutic agent of choice for the treatment of opiate addiction in pregnancy. The co-consumption (heroin, cocaine) which may influence the effects of methadone is frequent. Therefore, the impact of cocaine and heroin on the placental transfer of methadone and the placental tissue was investigated under in vitro conditions. Methods: Placentae (n = 24) were ex-vivo perfused with medium (m) (control, n = 6), m plus methadone (n = 6), m plus methadone and cocaine (n = 6) or m plus methadone and heroin (n = 6). Placental functionality parameters like antipyrine permeability, glucose consumption, lactate production, hormone production (hCG and leptin), microparticles release and the expression of P-glycoprotein were analysed.
Journal of Analytical Toxicology, 2009
A validated method for quantifying methadone, 2-ethylidene-1,5-dimethyl-3,3diphenylpyrrolidine, cocaine, benzoylecgonine, 6-acetylmorphine, morphine, and codeine in human placenta by liquid chromatography-ion trap mass spectrometry is described. Specimens (1 g) were homogenized and subjected to solid-phase extraction. Chromatographic separation was performed on a Synergi Polar RP column with a gradient of 0.1% formic acid and acetonitrile. The method was linear from 10 to 2000 ng/g for methadone and 2.5 to 500 ng/g for other analytes. Limits of detection were 0.25-2.5 ng/g, imprecisions < 9.1%CV, analytical recoveries 84.4-113.3%, extraction efficiencies > 46%, matrix effects −8.0-129.9%, and process efficiencies 24.2-201.0%. Method applicability was demonstrated by analysis of five placenta specimens from opioid-dependent women receiving methadone pharmacotherapy, with methadone doses ranging from 65 to 95 mg on the day of delivery. These are the first data on placenta concentrations of methadone and metabolites after controlled drug administration. Detection of other common drugs of abuse in placenta will also improve our knowledge of the usefulness of this matrix for detecting in utero drug exposure and studying disposition of drugs in the maternal-fetal dyad. * This analytical method was presented at the
Changes to methadone clearance during pregnancy
European Journal of Clinical Pharmacology, 2005
Objective Measurement of plasma methadone concentration to investigate the rate of clearance of methadone prescribed for heroin dependence in the first, second and third trimesters of pregnancy. A secondary objective was to evaluate the outcome of pregnancy. Methods Longitudinal within subject study of nine pregnant opioid dependent subjects prescribed methadone at the Leeds Addiction Unit, an outpatient community based treatment centre. Plasma concentration versus time data for methadone was collected during each trimester and post-partum for our subjects. Data was available for the first and second trimesters for 4/9 cases. All but one of the subjects provided data during the third trimester and data post-partum was collected from three respondents. Measurements of methadone levels in plasma were carried out using high performance liquid chromatography (HPLC). Results Trough mean plasma methadone concentrations reduced as the pregnancies progressed from 0.12 mg/L (first trimester) to 0.07 mg/L (third trimester). The weight-adjusted clearance rates gradually increased from a mean of 0.17 to 0.21 L/hr/kg during pregnancy, although patterns differed substantially between the nine women. An assessment of relative clearance of methadone using two patients for whom we have had all three CL values (trimester 1–3) demonstrated notable change of CL (P=0.056) over time. Eight of our subjects delivered (3 males), within two weeks of their due date the ninth (male) was premature (21 days). The mean length of gestation was 39.7 weeks (SD=10 days) and none of the neonates met criterion for ‘low birth weight’ mean 3094, SD 368 g). Five neonates spent time (0.5–28 days) in a special care baby unit (SCUBU) and 4 of these displayed signs of methadone withdrawal. Conclusions General Practitioners and hospital doctors should recognise the significant benefits of prescribing methadone for heroin-dependent women during pregnancy. We recommend that if a pregnant opioid user complains of methadone withdrawal symptoms (i.e. that the methadone dose does not “hold” them) the prescribing clinician takes this observation seriously and considers a more detailed assessment. Further work on key factors undergoing changes during pregnancy accounting for differences in methadone metabolism in the mother, fetus and neonate are required.
Maternal Methadone Dose, Placental Methadone Concentrations, and Neonatal Outcomes
Clinical Chemistry, 2011
BACKGROUND: Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadonemaintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs.
Fetal response to maternal methadone administration
American Journal of Obstetrics and Gynecology, 2005
Methadone Fetal development Substance abuse Pregnancy Fetal heart rate Fetal movement Objective: The purpose of this study was to investigate the effect of methadone on fetal neurobehavioral functions and maternal physiologic indicators. Study design: Forty women attending a substance abuse treatment facility with otherwise uncomplicated pregnancies were evaluated at peak and trough methadone levels. Fetal measures included heart rate, variability, periodic accelerations/decelerations, motor activity, and fetal movement-heart rate coupling. Maternal measures included maternal heart period, variability, electrodermal skin conductance, respiration, and respiratory sinus arrhythmia (RSA). Repeated measure analysis of variance was used to evaluate within-subject changes. Results: At peak methadone, fetal heart rate was slower, less variable, and displayed fewer accelerations. Fetuses displayed less motor activity, and the integration between heart rate and motor activity was attenuated. Maternal heart rate and skin conductance were unchanged, but methadone administration was associated with lower respiratory rate and RSA, an indicator of parasympathetic tone. Conclusion: Maternal methadone administration has significant effects on fetal behavioral functions that are independent of maternal effects.