| Autor: |
Marques, Maria Paula, Coelho, Eduardo Barbosa, Dos Santos, Neife Aparecida Guinaim, Geleilete, Tufik José Magalhães, Lanchote, Vera Lucia |
| Předmět: |
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| Zdroj: |
European Journal of Clinical Pharmacology; Dec2002, Vol. 58 Issue 9, p607-614, 8p |
| Abstrakt: |
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) 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): Cmax 3.9 (1.7–6.1) ng ml–1 versus 0.7 (0.4–1.0) ng ml–1, AUC0–24 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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