Bupropion metabolism by human placenta (original) (raw)
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Transplacental transfer and metabolism of bupropion
Journal of Maternal-fetal & Neonatal Medicine, 2009
Objective-In order to evaluate the potential use of bupropion as smoking cessation therapy during pregnancy, the aim of this investigation was to determine transplacental transfer and metabolism of bupropion and its distribution among placental tissue and maternal and fetal circuits of the dually perfused placental lobule.
Transplacental Transfer and Metabolism of Buprenorphine in Preterm Human Placenta
American Journal of Perinatology, 2011
Objective-In order to evaluate the potential use of bupropion as smoking cessation therapy during pregnancy, the aim of this investigation was to determine transplacental transfer and metabolism of bupropion and its distribution among placental tissue and maternal and fetal circuits of the dually perfused placental lobule.
Metabolism of bupropion by baboon hepatic and placental microsomes
Biochemical Pharmacology, 2011
The aim of this investigation was to determine the biotransformation of bupropion by baboon hepatic and placental microsomes, identify the enzyme(s) catalyzing the reaction(s) and determine its kinetics. Bupropion was metabolized by baboon hepatic and placental microsomes to hydroxybupropion (OH-BUP), threo-(TB) and erythrohydrobupropion (EB). OH-bupropion was the major metabolite formed by hepatic microsomes (K m 36 ± 6 µM, Vmax 258 ± 32 pmol mg protein −1 min −1 ), however the formation of OH-BUP by placental microsomes was below the limit of quantification. The apparent K m values of bupropion for the formation of TB and EB by hepatic and placental microsomes were similar. The selective inhibitors of CYP2B6 (ticlopidine and phencyclidine) and monoclonal antibodies raised against human CYP2B6 isozyme caused 80% inhibition of OH-BUP formation by baboon hepatic microsomes. The chemical inhibitors of aldo-keto reductases (flufenamic acid), carbonyl reductases (menadione), and 11β-hydroxysteroid dehydrogenases (18β-glycyrrhetinic acid) significantly decreased the formation of TB and EB by hepatic and placental microsomes. Data indicate that CYP2B of baboon hepatic microsomes is responsible for biotransformation of bupropion to OH-BUP, while hepatic and placental short chain dehydrogenases/reductases and to a lesser extent aldo-keto reductases are responsible for the reduction of bupropion to TB and EB.
Biochemical Pharmacology, 2010
Cigarette smoking during pregnancy is a preventable risk factor associated with maternal and fetal complications. Bupropion is an antidepressant used successfully for smoking cessation in nonpregnant patients. Our goal is to determine whether it could benefit the pregnant patient seeking smoking cessation. The aim of this investigation was to determine the role of human placenta in the disposition of bupropion and its major hepatic metabolite, OH-bupropion. The expression of efflux transporters P-gp and BCRP was determined in placental brush border membrane (n = 200) and revealed a positive correlation (p < 0.05). Bupropion was transported by BCRP (K t 3 μM, V max 30pmol/mg protein/min) and P-gp (K t 0.5 μM, V max 6 pmol/mg protein*min) in placental inside out vesicles (IOVs). OH-bupropion crossed the dually-perfused human placental lobule without undergoing further metabolism, nor was it an efflux substrate of P-gp or BCRP. In conclusion, our data indicate that human placenta actively regulates the disposition of bupropion (via metabolism, active transport), but not its major hepatic metabolite, OH-bupropion.
Deeper Insight into the Reducing Biotransformation of Bupropion in the Human Liver
Drug Metabolism and Pharmacokinetics, 2014
Bupropion is widely used as an antidepressant drug and also as a smoking cessation aid. In humans, this drug is extensively metabolized to form several metabolites. Oxidised hydroxybupropion and two reduced metabolites, threohydrobupropion and erythrohydrobupropion, are major metabolites. All of these metabolites are considered to be active. Although the oxidative metabolic pathway and the central role of CYP2B6 are known, the enzymes that participate in the reduction have not been identified to date. The aim of this study was to confirm the role of human liver subcellular fractions in the metabolism of bupropion and elucidate the contribution of particular carbonyl-reducing enzymes. An HPLC method for the determination of bupropion metabolites was utilised. Bupropion is reduced to threohydrobupropion and less to erythrohydrobupropion in human liver cytosol, microsomes and also mitochondria. Surprisingly, intrinsic clearance for formation of both metabolites is the highest in mitochondrial fraction. Moreover this study provides the first direct evidence that 11¢-hydroxysteroid dehydrogenase 1, AKR1C1, AKR1C2, AKR1C3 and CBR1 participate in the reducing biotransformation of bupropion in vitro. The enzyme kinetics of all of these reductases was investigated and kinetic parameters were calculated.
Journal of Pharmaceutical and Biomedical Analysis, 2012
A liquid chromatography in tandem with electro-spray ionization mass spectrometry method has been developed and validated for the quantitative determination of BUP and its major metabolites (hydroxybupropion, threo-and erythrohydrobupropion) in human umbilical cord plasma and placental tissue. The samples were acidified with trichloroacetic acid, and protein precipitated by adding acetonitrile. Chromatographic separation of drug and metabolites was achieved by using a Waters Symmetry C 18 column, with an isocratic elution of 31% methanol and 69% formic acid (0.04%, v/v) aqueous solution at a flow rate of 1.0 mL/min. Detection was carried out by mass spectrometry using positive electro-spray ionization mode, and the compounds were monitored using multiple reactions monitoring method. Deuterium-labeled isotopes of the compounds were used as internal standards. Calibration curves were linear (r 2 >0.99) in the tested ranges. The lower limit of quantification of analytes in umbilical cord plasma samples is < 0.72 ng/mL and 0.92 ng/g in placental tissue samples. The relative deviation of this method was < 15% for intra-and interday assays, and the accuracy ranged between 88 and 105%. The extraction recovery of the four analytes ranged between 89 and 96% in umbilical cord plasma, and 64 and 80% in placental tissue. No significant matrix effect was observed in the presented method.
American Journal of Perinatology, 2014
Cigarette smoking during pregnancy is one of the leading preventable causes of low birth weight 1 and is associated with multiple other adverse outcomes, such as fetal growth restriction, preterm birth, spontaneous abortions, stillbirth, and potential increased risk of neurodevelopmental disorders. 2,3 Despite risks, between 5.2 and 35.7% of the U.S. women smoke through pregnancy, with an average estimate of 14.6%. 4 Annual U.S. health care costs because of effects of prenatal smoking on neonatal outcomes were estimated at 263to366million,5andincreasedto263 to 366 million, 5 and increased to 263to366million,5andincreasedto593 to 706 million over the first year of life 6 in 1995 and 1996 dollars, respectively. Smoking cessation in pregnancy has been estimated to prevent up to 5% of perinatal deaths, 20 to 30% of low birth weight births, and 15% of preterm deliveries. 7,8 Quitting even in the last trimester is clinically meaningful, as smoking in the third trimester has the greatest impact on birth weight. 9
Aromatase Is the Major Enzyme Metabolizing Buprenorphine in Human Placenta
Journal of Pharmacology and Experimental Therapeutics, 2003
Buprenorphine (BUP) is a partial opiate agonist used for treatment of the adult and the pregnant addicted to this class of narcotics. The kinetic parameters for transplacental transfer and the metabolism of BUP during its perfusion in a placental lobule were the subject of an earlier report from our laboratory. The aim of this investigation is to identify and characterize the enzyme catalyzing the metabolism of BUP in term human placenta. Norbuprenorphine (norBUP) is the only metabolite formed as determined by high performance liquid chromatography and mass spectrometry. The activity of the enzyme responsible for BUP metabolism is highest in the microsomal fraction and lowest in the cytosolic, with the mitochondrial in between. Compounds with selective affinity to the enzyme aromatase (CYP 19), namely 4-hydroxyandrostenedione and
Metabolism and disposition of bupropion in pregnant baboons (Papio cynocephalus)
Drug metabolism and disposition: the biological fate of chemicals, 2014
Recent in vitro data obtained in our laboratory revealed similarities between baboons and humans in the biotransformation of bupropion (BUP) by both hepatic and placental microsomes. These data supported the use of baboons to study BUP biotransformation during pregnancy. The aim of this investigation was to determine the pharmacokinetics of BUP in baboons during pregnancy and postpartum, as well as fetal exposure to the drug after intravenous administration. Pregnant baboons (n = 5) received a single intravenous bolus dose of bupropion hydrochloride (1 mg/kg) at gestational ages 94-108 days (midpregnancy), 142-156 days (late pregnancy), and 6 weeks postpartum. Blood and urine samples were collected for 12 and 24 hours, respectively. The concentrations of BUP, hydroxybupropion (OH-BUP), threohydrobupropion, and erythrohydrobupropion in plasma were determined by liquid chromatography-tandem mass spectrometry. Relative to the postpartum period, the average midpregnancy clearance of BUP...
European Journal of Drug Metabolism and Pharmacokinetics, 1988
Placental and hepatic xenobiotic-metabolising activities were studied in smokers and non-smokers, who were classified by anamnestic interview, plasma thiocyanate and plasma cotinine determinations. Plasma thiocyanate assay is inadequate in the classification of smokers and non-smokers. Plasma cotinine levels reflect more accurately the smoking status. The anamnestic smokers remained smokers and several self-declared non-smokers proved to be smokers. On the basis of plasma cotinine determination all real smokers had higher 7-ethoxyresorufin O-deethylase (ERDE) activities measured either in placental microsomes or liver biopsy homogenates than non-smokers. Classification based on plasma cotinine levels showed a statistically significant (P<O.OOI) difference between smokers and non-smokers in liver homogenate ERDE activity. However, cotinine levels did not correlate with any of the xenobiotic-metabolising activities tested. An objective biochemical marker, such as cotinine determination seems to be necessary when evaluating the effect of smoking on drug metabolism in man.