Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients

AimTo investigate the influence of gestational diabetes mellitus (GDM) on the kinetic disposition and transplacental and amniotic fluid distribution of metoprolol and its metabolites O-desmethylmetoproloic acid and -hydroxymetoprolol stereoisomers in hypertensive parturients receiving a single dose of the racemic drug. MethodsThe study was conducted on hypertensive parturients with well-controlled GDM (n = 11) and non-diabetic hypertensive parturients (n = 24), all receiving a single 100mg oral dose of racemic metoprolol tartrate before delivery. Serial maternal blood samples (0-24h) and umbilical blood and amniotic fluid samples were collected for the quantitation of metoprolol and its metabolite stereoisomers using LC-MS/MS or fluorescence detection. ResultsThe kinetic disposition of metoprolol and its metabolites was stereoselective in the diabetic and control groups. Well-controlled GDM prolonged t(max) for both enantiomers of metoprolol (1.5 vs. 2.5h R-(+)-MET; 1.5 vs. 2.75h S-(-)-MET) and O-desmethylmetoproloic acid (2.0 vs. 3.5h R-(+)-AOMD; 2.0 vs. 3.0h S-(-)-OAMD), and for the four stereoisomers of -hydroxymetoprolol (2.0 vs. 3.0h for 1S,2R-, 1R,2R- and 1R,2S-OHM; 2.0 vs. 3.5h for 1S,2S-OHM) and reduced the transplacental distribution of 1S,2S-, 1R,2R-, and 1R,2S-OHM by approximately 20%. ConclusionsThe kinetic disposition of metoprolol was enantioselective, with plasma accumulation of the S-(-)-MET eutomer. Well-controlled GDM prolonged the t(max) of metoprolol and O-desmethylmetoproloic acid enantiomers and the -hydroxymetoprolol stereoisomers and reduced by about 20% the transplacental distribution of 1S,2S-, 1R,2R-, and 1R,2S-OHM. Thus, well-controlled GDM did not change the activity of CYP2D6 and CYP3A involved in metoprolol metabolism.