title: Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients.
abstract: OBJECTIVE
  To 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 α-hydroxymetoprolol stereoisomers in hypertensive parturients receiving a single dose of the racemic drug.
  
  
  METHODS
  The study was conducted on hypertensive parturients with well-controlled GDM (n = 11) and non-diabetic hypertensive parturients (n = 24), all receiving a single 100 mg oral dose of racemic metoprolol tartrate before delivery. Serial maternal blood samples (0-24 h) 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.
  
  
  RESULTS
  The kinetic disposition of metoprolol and its metabolites was stereoselective in the diabetic and control groups. Well-controlled GDM prolonged tmax for both enantiomers of metoprolol (1.5 vs. 2.5 h R-(+)-MET; 1.5 vs. 2.75 h S-(-)-MET) and O-desmethylmetoproloic acid (2.0 vs. 3.5 h R-(+)-AOMD; 2.0 vs. 3.0 h S-(-)-OAMD), and for the four stereoisomers of α-hydroxymetoprolol (2.0 vs. 3.0 h for 1'S,2R-, 1'R,2R- and 1'R,2S-OHM; 2.0 vs. 3.5 h for 1'S,2S-OHM) and reduced the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM by approximately 20%.
  
  
  CONCLUSIONS
  The kinetic disposition of metoprolol was enantioselective, with plasma accumulation of the S-(-)-MET eutomer. Well-controlled GDM prolonged the tmax of metoprolol and O-desmethylmetoproloic acid enantiomers and the α-hydroxymetoprolol stereoisomers and reduced by about 20% the transplacental distribution of 1'S,2S-, 1'R,2R-, and 1'R,2S-OHM. Thus, well-controlled GDM did not change the activity of CYP2D6 and CYP3A involved in metoprolol metabolism.
authors.affiliation: Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Natalícia de Jesus
authors.initials: Nde J
authors.lastname: Antunes
authors.forename: Ricardo Carvalho
authors.initials: RC
authors.lastname: Cavalli
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.forename: Elaine Christine Dantas
authors.initials: EC
authors.lastname: Moisés
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000097:blood* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D016640:Diabetes, Gestational / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D005312:Fetal Blood / Q000737:chemistry; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007231:Infant, Newborn; D008790:Metoprolol / Q000097:blood* / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D036801:Parturition; D010920:Placenta / Q000378:metabolism*; D011247:Pregnancy; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D000959:Antihypertensive Agents; D008790:Metoprolol
keywords: arterial hypertension; enantiomers; gestational diabetes mellitus; metoprolol; parturients; pharmacokinetics