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

Abstract

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 α-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 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. RESULTSThe 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. CONCLUSIONSThe 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.

A method to determine pharmacokinetic parameters based on andante constant-rate intravenous infusion

“…In addition, the range of the terminal elimination phase involved in the regression is specified by the individual user, which leads to an arbitrary estimation, and becomes even worse if the error is high. 5 , 6 In the other hand, the mean residence time ( MRT ) determined by the AUMC/AUC merely demonstrates the characteristic of the central compartment or blood, but it cannot sufficiently present the drug exposure in the whole organism. As a result, the equation t 1/2 = 69.3%· MRT is false other than for drugs of the one-compartment model.…”

Imbalance of Drug Transporter-CYP450s Interplay by Diabetes and Its Clinical Significance

“…Similarly, pregnant women with gestational diabetes showed significantly higher C max and AUC of lidocaine following peridural anesthesia administration of lidocaine than non-diabetic patients [61]. However, oral plasma concentrations of nifedipine [62] and metoprolol [63] in pregnant women with gestational diabetes were comparable to those in non-diabetic pregnant women. Adith et al [64] investigated phenytoin kinetics in 10 male type 1 and 10 type 2 diabetic patients.…”

Recent applications of CE‐ and HPLC‐MS in the analysis of human fluids

“…Finally, (v) metoprolol, a racemic drug used for the treatment of hypertension during pregnancy, was detected by Antunes et al. applying LC‐MS/MS or LC with fluorescence detection to investigate the influence of gestational diabetes mellitus on its kinetic disposition and transplacental and AF distribution.…”