OBJECTIVE:Nisoldipine (N) is a dihydropyridine calcium antagonist marketed as a racemic mixture and used for the treatment of hypertension. In the present study, we investigated the influence of type-2 diabetes mellitus (DM) on the enantioselective pharmacokinetic and dynamic parameters of N. METHODS: Seventeen hypertensive patients, nine of them with DM, were investigated in a cross-over study with administration of rac-N as coat-core tablets (20 mg day(-1)) orplacebo for 15 days each. Serial blood samples (0-24 h) were collected on the 15th day, and 24-h ambulatory blood pressure (BP) monitoring was simultaneously evaluated. N enantiomers in plasma samples were analysed using chiral high-performance liquid chromatography combined with gas chromatography/mass spectrometry. The enantiomeric ratios differing from one were evaluated using the Wilcoxon test, and the results are reported as means with the 95% confidence intervals. A lidocaine (L) test was carried out as an in vivo marker of CYP3A4 (and CYP1A2) activities. RESULTS: The following differences were observed between the (+)-N and (-)-N enantiomers, respectively, in the patients presenting with DM (means and ranges): C(max) 3.9 (1.7-6.1) ng ml(-1) versus 0.7 (0.4-1.0) ng ml(-1), AUC(0-24) 51.5 (29.0-74.0) ng ml(-1) h versus 9.4 (5.9-12.8) ng ml(-1) h, and Cl/f 3.6 (1.9-5.4) l h(-1) kg(-1) versus 18.7 (11.7-25.7) l h(-1) kg(-1). The Cl/f value of (+)-N was lower (Mann-Whitney test) in patients with DM: 6.0 (4.3-7.5) l h(-1) kg(-1) versus 3.6 (1.9-5.4) l h(-1) kg(-1). The same observation was made for the (-)-N, with Cl/f reaching 38.8 (26.8-51.0) l h(-1) kg(-1) and 18.7 (11.7-25.7) l h(-1) kg(-1) for the non-diabetic and DM groups, respectively. The L test resulted in higher ratios (P < 0.05) of plasma L/MEGX concentrations (30 min after i.v. L) for DM (11.1 vs 18.6). N significantly reduced systolic and diastolic BP (P < 0.05, Wilcoxon test) in all patients investigated relative to placebo. No differences in BP reduction were observed between diabetic and non-diabetic patients. N significantly increased noradrenaline concentrations in plasma of both patient groups. The data also demonstrated that the plasma concentrations of noradrenaline 30 min after N administration were lower (P < 0.05) in diabetic (mean 2.86 pmol ml(-1)) than in non-diabetic patients (4.80 pmol ml(-1)). CONCLUSIONS: The present data permit us to infer that type-2 diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N distomer, presumably due to a lower activity of CYP3A4, although it does not modify the clinical effect brought about by the reduction in BP.
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OBJECTIVE:Nisoldipine (N) is a dihydropyridine calcium antagonist marketed as a racemic mixture and used for the treatment of hypertension. In the present study, we investigated the influence of type-2 diabetes mellitus (DM) on the enantioselective pharmacokinetic and dynamic parameters of N. METHODS: Seventeen hypertensivepatients, nine of them with DM, were investigated in a cross-over study with administration of rac-N as coat-core tablets (20 mg day(-1)) or placebo for 15 days each. Serial blood samples (0-24 h) were collected on the 15th day, and 24-h ambulatory blood pressure (BP) monitoring was simultaneously evaluated. N enantiomers in plasma samples were analysed using chiral high-performance liquid chromatography combined with gas chromatography/mass spectrometry. The enantiomeric ratios differing from one were evaluated using the Wilcoxon test, and the results are reported as means with the 95% confidence intervals. A lidocaine (L) test was carried out as an in vivo marker of CYP3A4 (and CYP1A2) activities. RESULTS: The following differences were observed between the (+)-N and (-)-N enantiomers, respectively, in the patients presenting with DM (means and ranges): C(max) 3.9 (1.7-6.1) ng ml(-1) versus 0.7 (0.4-1.0) ng ml(-1), AUC(0-24) 51.5 (29.0-74.0) ng ml(-1) h versus 9.4 (5.9-12.8) ng ml(-1) h, and Cl/f 3.6 (1.9-5.4) l h(-1) kg(-1) versus 18.7 (11.7-25.7) l h(-1) kg(-1). The Cl/f value of (+)-N was lower (Mann-Whitney test) in patients with DM: 6.0 (4.3-7.5) l h(-1) kg(-1) versus 3.6 (1.9-5.4) l h(-1) kg(-1). The same observation was made for the (-)-N, with Cl/f reaching 38.8 (26.8-51.0) l h(-1) kg(-1) and 18.7 (11.7-25.7) l h(-1) kg(-1) for the non-diabetic and DM groups, respectively. The L test resulted in higher ratios (P < 0.05) of plasma L/MEGX concentrations (30 min after i.v. L) for DM (11.1 vs 18.6). N significantly reduced systolic and diastolic BP (P < 0.05, Wilcoxon test) in all patients investigated relative to placebo. No differences in BP reduction were observed between diabetic and non-diabeticpatients. N significantly increased noradrenaline concentrations in plasma of both patient groups. The data also demonstrated that the plasma concentrations of noradrenaline 30 min after N administration were lower (P < 0.05) in diabetic (mean 2.86 pmol ml(-1)) than in non-diabeticpatients (4.80 pmol ml(-1)). CONCLUSIONS: The present data permit us to infer that type-2 diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N distomer, presumably due to a lower activity of CYP3A4, although it does not modify the clinical effect brought about by the reduction in BP.
Authors: Dan Xu; Feng Li; Mian Zhang; Ji Zhang; Can Liu; Meng-yue Hu; Ze-yu Zhong; Ling-ling Jia; Da-wei Wang; Jie Wu; Li Liu; Xiao-dong Liu Journal: Acta Pharmacol Sin Date: 2014-08-25 Impact factor: 6.150
Authors: Teresa Maria J P Carvalho; Ricardo de Carvalho Cavalli; Sérgio P Cunha; Cláudia O de Baraldi; Maria P Marques; Natalícia J Antunes; Ana Leonor P C Godoy; Vera Lucia Lanchote Journal: Eur J Clin Pharmacol Date: 2010-09-17 Impact factor: 2.953
Authors: Elaine Christine Dantas Moisés; Luciana de Barros Duarte; Ricardo de Carvalho Cavalli; Maria Paula Marques; Vera Lúcia Lanchote; Geraldo Duarte; Sérgio Pereira da Cunha Journal: Eur J Clin Pharmacol Date: 2008-08-06 Impact factor: 2.953