Bioequivalence of Two Tablet Formulations of Nadolol Using Single and Multiple Dose Data: Assessment Using Stereospecific and Nonstereospecific Assays

Abstract

Nadolol, a nonspecific beta-blocker, is a racemate composed of equal amounts of four stereoisomers, namely, SQ-12148, SQ-12149, SQ-12150, and SQ-12151. In an open-label, randomized, four-period crossover study, the pharmacokinetics of nadolol and its stereoisomers and the bioequivalence of two formulations of nadolol were assessed in 20 healthy male subjects following a single dose (80 mg) and multiple doses (80 mg; once daily for 7 days). A standard granulated tablet and direct compressed tablet formulations, each containing 80 mg of nadolol, with different in vitro dissolution profiles that met current USP requirements were used. The four treatments were single and multiple doses of granulated tablet, and single and multiple doses of compressed tablet. There was a 7 day washout period between successive treatments. All doses of nadolol were administered after an overnight fast. Serial blood samples were collected up to 72 h following the single dose and during multiple dose treatments, following day 6 and 7 doses. Validated high-performance liquid chromatographic assays were applied to measure nadolol and its stereoisomers in the study samples. Plasma concentration data were subjected to noncompartmental pharmacokinetic analysis. Both C(max) and AUC values were significantly greater for SQ-12150 when compared to other nadolol stereoisomers obtained after a single dose or at steady state. However, T(max) and T1/2 values were similar among the four isomers. The observed steady state AUC tau values for nadolol (2278-2331 ng h/ML) or its stereoisomers (550-874 ng h/ML) were significantly greater than those predicted from the single dose AUCinf values (nadolol, 1840-1845 ng h/ML; isomers, 450-713 ng h/ML). The intrasubject variability, computed from multiple dose data, was generally greater for the stereoisomers (17-40%) than for nadolol (10-32%). The two formulations were bioequivalent for nadolol (C(max) = 0.98 [84%, 117%]; AUCinf = 1.03 [93%, 116%]) and SQ-12150 (C(max) = 1.12 [89%, 122%]; AUCinf = 0.98 [82%, 119%]) after a single dose, and only for nadolol (C(max) = 1.07 [84%, 118%]; AUCinf = 1.02 [91%, 113%]) at steady state.

Preparation of 2R, 3S, 2′R-nadolol enantiomer using S-(-)-menthyl chloroformate as a chiral derivatizing reagent

“…Nadolol diastereomers in plasma were extracted by solid phase extraction method (Hoshino et al, 1994b;Belas et al, 1995) or extracted by liquidliquid extraction method and derivatized with chiral derivatizing reagent R-(-)-1-(1-naphthyl)ethylisocyanate to form urea derivatves followed by determined by achiral reversed phase HPLC. And this method was applied to the bioequivance of two tablet formulations of nadolol using single and multiple dose datas from stereospecific and nonstereospecific assay (Srinivas et al, 1996). Nadolol isomers were separated by capillary electrophoresis using sulfated β-cyclodextrins (Tamisier-Karolak et al, 1999), separated by chiral micellar electrokinetic chromatography using polymeric alkeoxy amino acid surfactants (Rizvi et al, 2004) and analysed using capillary electrochromatography-mass spectrometry with a vancomycin stationary phase (Bragg et al, 2008).…”

Cromatografia líquida com fase quiral aplicada na separação enantiomérica de fármacos cardiovasculares

“…Atenolol, betaxolol, metoprolol, nadolol e pindolol são agentes bloqueadores de receptores β-adrenérgicos empregados principalmente, na angina pectoris, hipertensão, certas arritmias cardíacas e no tratamento do glaucoma (Darmon, Thenot, 1986;Foye, 1989;Hoffman, Lefkowitz, 1996;Krstulovic et al, 1988;Mehvar, Brocks, 2001;Srinivas et al, 1996;Zhang, Stewart, Ujhelyi, 1995).…”

“…Suas estruturas químicas podem ser vistas na Figura 1, onde pelo menos um centro quiral está presente na porção α-hidroxietilamina (aminoálcool). Faz exceção o nadolol, que possui três centros quirais (Belas et al, 1995;Mehvar, Brocks, 2001;Srinivas et al, 1996;Aboul-Enein, AbouBasha, 1996). A maioria dos agentes β-bloqueadores freqüentemente prescritos é formulada e comercializada na forma racêmica, embora, para alguns deles, já tenha sido demonstrado que o enantiômero (S)-é o responsável pelo efeito farmacológico principal (Mehvar, Brocks, 2001).…”

Separação, obtenção e utilização de enantômeros puros no controle estereoespecífico de qualidade de medicamentos contendo bisoprolol

“…Os dados disponíveis na literatura sobre a atividade farmacológica dos -bloqueadores indicam que a interação destes agentes com receptores -adrenérgicos é altamente estereoespecífica (43,49,73) . Normalmente, a atividade -bloqueadora cardíaca é devida ao isômero S, sendo que a razão de atividade entre os enantiômeros pode ser altamente variável.…”

“…A técnica tem sido amplamente aplicada na determinação da pureza óptica e da constituição isomérica de medicamentos, matérias-primas, preparações farmacêuticas e fluídos biológicos (1,2,3,14,15,25,26,39,53,55,62,64,73,75,78,83,85) , estudos de instabilidade configuracional de fármacos (racemização, enantiomerização, epimerização) (23,24,25,35) e determinação da farmacocinética e em estudos de metabolismo de fármacos (12,21) . contribuem para a enantiosseletividade (7,19,61,62,70) .…”