Enantioselectivity in the steady‐state pharmacokinetics and transplacental distribution of pindolol at delivery in pregnancy‐induced hypertension

Abstract

Nine patients taking oral doses of 10 mg/12 h rac-pindolol as part of their treatment for hypertension in pregnancy were recruited for the study. Maternal and fetal gestational age ranged from 20-38 years and 28-41 weeks, respectively. Blood was collected from the umbilical cord vein and from the mother from zero to 12 h after drug administration. Urine was collected for 12 h after rac-pindolol administration at the following intervals: 0-3, 3-6, 6-9, and 9-12 h. Plasma and urine concentrations of the pindolol enantiomers were determined by HPLC using a Chiralpak AD chiral column and fluorescence detection. The data were fitted to a one-compartment model and differences between (+)-R and (-)-S enantiomers were compared by the paired t-test (P < 0.05). Mean results are reported. The disposition of pindolol in maternal plasma was stereoselective, with higher AUC(SS)0-12 (84.34 vs. 95.69 ng.h/ml) and Cl(R) values (9.16 vs. 10.85 L/h) and lower Vd/f (251.38 vs. 225.17 L) and Cl/f (62.48 vs. 55.74 L/h) for the (+)-R pindolol. The transplacental distribution of pindolol was not stereoselective. Cord, plasma, and presumably fetal, concentrations of the pindolol enantiomers were 56% of the maternal plasma concentrations up to 6 h after the last dose.

Análise enantiosseletiva de fármacos: contribuições da cromatografia líquida de alta eficiência e eletroforese capilar

“…As referências já citadas nesse texto 44,48,52,[89][90][91][92][93][94][95]100,104,110 e algumas outras publicações recentes [121][122][123][124] demostram o grande envolvimento desses grupos na análise enantiosseletiva de fármacos e metabólitos em materiais biológi-cos. Como as análises são feitas em matrizes biológicas complexas e analitos presentes em quantidades muito baixas, também estão sendo desenvolvidos e validados novos procedimentos de preparação da amostra como, por ex., a microextração em fase sóli-da 110 . Graças a esses métodos desenvolvidos, vários estudos de disposição cinética estão sendo realizados, possibilitando estabelecer a influência de várias doenças e aspectos genéticos na disposição cinética de fármacos quirais, sendo citados apenas os mais recentes [125][126][127][128][129] . Um outro grupo, do Instituto de Química da Universidade Federal de São Carlos, atua no desenvolvimento de novas fases estacionárias quirais e modos de separação e, mais recentemente, em aplicações na análise de fármacos quirais em materiais biológicos.…”

Determination of pindolol enantiomers in amniotic fluid and breast milk by high-performance liquid chromatography: Applications to pharmacokinetics in pregnant and lactating women

“…The pharmacokinetics and transplacental distribution of pindolol enantiomers at delivery in pregnancy-induced hypertension were reported only in a study by Gonçalves et al [8].…”

“…Pindolol crosses the placenta, with cord to maternal serum ratios at 2 and 6 h after the last dose equal to 0.4 and 0.7, respectively [1]. The transplacental distribution of pindolol was reported not to be stereoselective [8].…”

“…Indirect methods for the analysis of pindolol enantiomers employ (−)-S-␣-methylbenzyl isocyanate [5,6,12,13] or 2,3,4,6-tetra-O-acetyl-␤-d-glucopyranosyl isothiocyanate [14] for the formation of pindolol diastereoisomers which are separated on a reverse-phase C-18 column, with quantitation limits of 2.0-10.0 ng/mL plasma for both enantiomers. Direct methods use chiral columns consisting of ␣ 1 -acid glycoprotein [15], cellulose tris(3,5-dimethylphenyl carbamate) (Chiralcel ODR) [7], or amylose tris-(3,5-dimethylphenylcarbamate) (Chiralpak AD) [8], with detection limits of 1.2-0.5 ng/mL of (+)-R-pindolol and 4.3-0.5 ng/mL of (−)-S-pindolol in serum, and 21.0-5.0 ng/mL of (+)-R-pindolol and 76.0-5.0 ng/mL of (−)-S-pindolol in urine.…”

Pharmacokinetic Development of a Sensitive and Stereoselective HPLC Method for the Analysis of Pindolol in Plasma and Pharmaceutical Products Using a Chiralpak IB Column and Fluorescence Detection

“…Indirect methods for the analysis of pindolol enantiomers employ S-(−)-α-methylbenzyl isocyanate [26,27] or 2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl isothiocyanate [28] for the formation of pindolol diastereoisomers which are separated on a reverse-phase C-18 column. Direct methods use chiral columns consisting of α 1 -acid glycoprotein [29], cellulose tris(3,5-dimethylphenyl carbamate) (Chiralcel ODR) [30], or amylose tris(3,5-dimethylphenylcarbamate) (Chiralpak AD) [31]. Orazio et al, used vancomycin fused silica capillary for the enantiomeric resolution of pindolol [32].…”