Influence of gestational Diabetes mellitus on the enantioselective kinetic disposition and metabolism of metoprolol in hypertensive parturients

Author(s)

Natalicia de Jesus Antunes

• Document type: Master's Dissertation
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC)
• Defense date: 2010-10-20

Examining board members

Vera Lucia Lanchote; Ricardo de Carvalho Cavalli; Evandro José Cesarino

• Advisor: Vera Lucia Lanchote

Abstract

Metoprolol is a drug accepted in the treatment of hypertension during pregnancy and it is clinically available as a racemic mixture of its enantiomers S-(-) and R-(+) metoprolol, although S-(-)-metoprolol is considered the eutomer responsible for 1 adrenergic receptor blockade.This study evaluates the influence of gestational Diabetes mellitus on the kinetic disposition and metabolism of metoprolol enantiomers in hypertensive parturients. The investigated parturients (n=35) presented gestational age within 35 to 42 weeks, were phenotyped as extensive metabolizers of metoprolol and were distributed in the control group (n=24) or in the gestational Diabetes mellitus group (n =11). The parturients were treated with single oral dose of 100 mg racemic metoprolol tartrate 1-11 h before delivery. Maternal blood samples were collected until 24h after drug administration, whereas maternal blood, umbilical cord blood and amniotic fluid were simultaneously collected at delivery. Metoprolol enantiomers and its metabolites were quantified by LC-MS/MS or by fluorescence detection. Kinetic disposition of metoprolol is enantioselective in hypertensive parturients with observation of higher plasma concentrations (AUC0- 113.42 vs 62.65 ng.h/mL) and lower apparent total clearance (344.21 vs 623.14 L/h) for the S-(-)-metoprolol eutomer. The formation of -hydroxymetoprolol metabolite is also stereoselective in favor of the new chiral center 1\'R (AUC0- 1\'R/1\'S = 2.84). The formation in favor of R-(+)-metoprolol acid metabolite (AUC0- 2.77 vs 2.66 g.h/mL) explains the plasma accumulation of S-(-)-metoprolol. Gestational Diabetes mellitus prolongs tmax for both metoprolol enantiomers (1.5 vs 2.5 h), metoprolol acid metabolite (2.0 vs 3.5 h) and for all -hydroxymetoprolol isomers (2.0 vs 3.0 h). Gestational Diabetes mellitus does not alter the isomeric ratios of plasma concentrations of metoprolol, -hydroxymetoprolol and metoprolol acid metabolite. The concentrations of both metoprolol enantiomers (amniotic fluid/maternal plasma = 3.0 for R-(+)-metoprolol and 3.2 for the S-(-)-metoprolol) and -hydroxymetoprolol isomers (liquid amniotic fluid/maternal plasma = 5.1 for 1\'S,2R; 4.0 for 1\'S,2S; 1.6 for 1\'R,2R and 2.3 for 1\'R,2S) are higher in amniotic fluid than in maternal plasma. However, metoprolol acid metabolite enantiomers reach lower concentrations in amniotic fluid than in maternal plasma of hypertensive parturients (amniotic fluid/maternal plasma = 0.29 and 0.37 respectively for the R-(+)- and S-(-)- enantiomers). The transplacental distribution is approximately 1 for both enantiomers of metoprolol and all isomers of -hydroxymetoprolol and approximately 0.8 for both metoprolol acid metabolite enantiomers in hypertensive parturients. Gestational Diabetes mellitus reduces in approximately 20% the transplacental distribution of the isomers 1\'S,2S; 1\'R,2R and 1\'R,2S--hidroximetoprolol but does not alter the transplacental distribution of both metoprolol enantiomers. (AU)