Arne Reimers1, Grethe Helde2, Geir Bråthen3, Eylert Brodtkorb3. 1. Department of Clinical Pharmacology, St. Olavs University Hospital, 7006 Trondheim, Norway; Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489 Trondheim, Norway. 2. Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489 Trondheim, Norway. 3. Department of Neuroscience, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7489 Trondheim, Norway; Department of Neurology and Clinical Neurophysiology, St. Olavs University Hospital, 7006 Trondheim, Norway.
Abstract
PURPOSE: To investigate the physiological mechanisms behind the pronounced decline of lamotrigine (LTG) serum concentrations during pregnancy. METHODS: Serum and urine concentrations of LTG and its main metabolite, LTG-N2-glucuronide (LTG-GLUC), were measured monthly in 21 pregnancies of 19 women using LTG. Simultaneously, a panel of biochemical variables was monitored to evaluate liver and kidney function and possible hemodilution effects. Pharmacokinetic parameters were calculated once at baseline and once in gestational month 8. RESULTS: Initially, LTG and LTG-GLUC serum concentrations fell simultaneously by 27% and 38%, respectively (gestational month 2). Subsequently, the ratio of the LTG-GLUC/LTG serum concentrations increased gradually, correlating strongly with rising serum estradiol concentrations. In gestational month 8, the ratio was 164% higher than at baseline. At that time, LTG total clearance had increased by 118%, and the amount of unchanged LTG in urine had dropped by 40% while the amount of LTG-GLUC had increased by a corresponding 37%. CONCLUSIONS: The simultaneous decline of LTG and LTG-GLUC serum concentrations in early pregnancy suggests that in this phase, increased renal blood flow is the major cause. After gestational month 2, estradiol-induced glucuronidation of LTG becomes more important, leading to a further fall of LTG serum concentrations and a gradual rise of the LTG-GLUC/LTG-ratio through the remaining pregnancy. An expanded volume of distribution may also contribute to reduced LTG serum concentrations in pregnancy.
PURPOSE: To investigate the physiological mechanisms behind the pronounced decline of lamotrigine (LTG) serum concentrations during pregnancy. METHODS: Serum and urine concentrations of LTG and its main metabolite, LTG-N2-glucuronide (LTG-GLUC), were measured monthly in 21 pregnancies of 19 women using LTG. Simultaneously, a panel of biochemical variables was monitored to evaluate liver and kidney function and possible hemodilution effects. Pharmacokinetic parameters were calculated once at baseline and once in gestational month 8. RESULTS: Initially, LTG and LTG-GLUC serum concentrations fell simultaneously by 27% and 38%, respectively (gestational month 2). Subsequently, the ratio of the LTG-GLUC/LTG serum concentrations increased gradually, correlating strongly with rising serum estradiol concentrations. In gestational month 8, the ratio was 164% higher than at baseline. At that time, LTG total clearance had increased by 118%, and the amount of unchanged LTG in urine had dropped by 40% while the amount of LTG-GLUC had increased by a corresponding 37%. CONCLUSIONS: The simultaneous decline of LTG and LTG-GLUC serum concentrations in early pregnancy suggests that in this phase, increased renal blood flow is the major cause. After gestational month 2, estradiol-induced glucuronidation of LTG becomes more important, leading to a further fall of LTG serum concentrations and a gradual rise of the LTG-GLUC/LTG-ratio through the remaining pregnancy. An expanded volume of distribution may also contribute to reduced LTG serum concentrations in pregnancy.
Authors: Daniel Moj; Hugo Maas; André Schaeftlein; Nina Hanke; José David Gómez-Mantilla; Thorsten Lehr Journal: Clin Pharmacokinet Date: 2019-12 Impact factor: 6.447