529: Role of human placental UPD-glucuronosyltransferase in lamotrigine metabolism during pregnancy

ObjectiveDetermine if human placental UDP-glucuronosyltransferase (UGT) contributes to lamotrigine metabolism.Study DesignA descriptive cross-sectional study was designed to evaluate metabolic activity of placental UGT. Placental tissue from term, uncomplicated pregnancies was collected. Human placental microsomes (HPM) were isolated from placental tissues by serial differential centrifugation. Ethoxyresorufin O-deethylase (EROD) activity was utilized to confirm metabolic activity of the HPM. Placental microsomes were incubated with lamotrigine in varying concentrations. Liquid chromatography-mass spectrometry (LCMS) was utilized to determine presence of lamotrigine metabolite, lamotrigine glucuronide (LTG-G), by comparison to known standard curve concentrations of LTG-G.ResultsNine placentas were collected and processed; two from subjects with nicotine exposure during pregnancy. HPM of subjects exposed to nicotine exhibited induction of CYP1A enzyme by EROD activity, demonstrating presence of enzyme activity in HPM. In-vitro metabolism of lamotrigine to LTG-G by HPM was not detected by LCMS in either smokers or non-smokers.ConclusionHuman placental UGT does not contribute to lamotrigine metabolism at our defined level of detection. If a metabolic contribution from the placenta is present, it is likely not clinically significant. Levels of placental metabolism below our detection threshold should not account for the need for increased lamotrigine doseage requirements during gestation. ObjectiveDetermine if human placental UDP-glucuronosyltransferase (UGT) contributes to lamotrigine metabolism. Determine if human placental UDP-glucuronosyltransferase (UGT) contributes to lamotrigine metabolism. Study DesignA descriptive cross-sectional study was designed to evaluate metabolic activity of placental UGT. Placental tissue from term, uncomplicated pregnancies was collected. Human placental microsomes (HPM) were isolated from placental tissues by serial differential centrifugation. Ethoxyresorufin O-deethylase (EROD) activity was utilized to confirm metabolic activity of the HPM. Placental microsomes were incubated with lamotrigine in varying concentrations. Liquid chromatography-mass spectrometry (LCMS) was utilized to determine presence of lamotrigine metabolite, lamotrigine glucuronide (LTG-G), by comparison to known standard curve concentrations of LTG-G. A descriptive cross-sectional study was designed to evaluate metabolic activity of placental UGT. Placental tissue from term, uncomplicated pregnancies was collected. Human placental microsomes (HPM) were isolated from placental tissues by serial differential centrifugation. Ethoxyresorufin O-deethylase (EROD) activity was utilized to confirm metabolic activity of the HPM. Placental microsomes were incubated with lamotrigine in varying concentrations. Liquid chromatography-mass spectrometry (LCMS) was utilized to determine presence of lamotrigine metabolite, lamotrigine glucuronide (LTG-G), by comparison to known standard curve concentrations of LTG-G. ResultsNine placentas were collected and processed; two from subjects with nicotine exposure during pregnancy. HPM of subjects exposed to nicotine exhibited induction of CYP1A enzyme by EROD activity, demonstrating presence of enzyme activity in HPM. In-vitro metabolism of lamotrigine to LTG-G by HPM was not detected by LCMS in either smokers or non-smokers. Nine placentas were collected and processed; two from subjects with nicotine exposure during pregnancy. HPM of subjects exposed to nicotine exhibited induction of CYP1A enzyme by EROD activity, demonstrating presence of enzyme activity in HPM. In-vitro metabolism of lamotrigine to LTG-G by HPM was not detected by LCMS in either smokers or non-smokers. ConclusionHuman placental UGT does not contribute to lamotrigine metabolism at our defined level of detection. If a metabolic contribution from the placenta is present, it is likely not clinically significant. Levels of placental metabolism below our detection threshold should not account for the need for increased lamotrigine doseage requirements during gestation. Human placental UGT does not contribute to lamotrigine metabolism at our defined level of detection. If a metabolic contribution from the placenta is present, it is likely not clinically significant. Levels of placental metabolism below our detection threshold should not account for the need for increased lamotrigine doseage requirements during gestation.