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Enantioseletictive kinetic disposition of nisoldipine in hypertensive patients presenting with type 2 diabetes mellitus. Lidocaine used as a marker drug of CYP3A4

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Author(s):
Maria Paula Marques Pereira
Total Authors: 1
Document type: Doctoral Thesis
Press: São Paulo.
Institution: Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ)
Defense date:
Examining board members:
Vera Lucia Lanchote; Pierina Sueli Bonato; Luiz Fernando Lopes Guimaraes; Gilberto de Nucci; Silvia Regina Cavani Jorge Santos
Advisor: Vera Lucia Lanchote
Abstract

Nisoldipine is a dihydropyridine calcium antagonist marketed as a racemic mixture and used for the treatment of hypertension. ln the present study we investigated the influence of type-2 diabetes mellitus (DM) on the enantioselective pharmacokinetic and dynamic parameters of nisoldipine. Seventeen hypertensive patients, nine of them with DM, were investigated after administration of racemic nisoldipine as coat-core tablets (20 mg.day-1) for 15 days. Serial blood samples (0-24 h) were collected on the 15th day, and 24-h ambulatory blood pressure monitoring was simultaneously evaluated. Nisoldipine enantiomers in plasma samples were analysed using chiral highperformance liquid chromatography combined with gas chromatography/ mass spectrometry. The enantiomeric ratios differing from one were evaluated by the Wilcoxon test, and the results are reported as medians whith the 95 % confiance intervals. The lidocaine test carried out as an in vivo marker of activities of CYP3A4 (and CYP1A2) activities. The following differences were observed between the (+)-nisoldipine and (-)nisoldipine, respectively, in the patients presenting with DM (means and ranges): Cmax 3.0 (1.7-6.1) vs 0.5 (0.4-1.0) ng.ml-1, AUCSS0-24 44.0 (29.0-74.0) vs 7.9 (5.9-12.8) ng.ml-1.h., CI/F 3.4 (1.9-5.4) vs 18.3 (11.7-25.7) l.h-1.kg-1. The CI/F value of (+)-nisoldipine was lower (Mann-Whitney test) in patients with DM: 6.1 (4.3-7.5) vs 3.4 (1.9-5.4) l.h-1.kg-1. The same observation was made for the (-)-N, with CI/F reducing from 33.4 (26.8-51.0) to 18.3 (11.7-25.7) l.h-1.kg-1 for the non-diabetic and DM groups, respectively. The lidocaine test resulted in higher ratios (p<0.05) of plasma lidocaine/MEGX concentrations (30 min after i.v. lidocaine) for DM (10.8 vs 20.6). Nisoldipine significantly reduced systolic and diastolic blood pressure (BP) (p<0.05, Wilcoxon test) in all patients investigated compared to placebo. No significant differences in BP reduction were observed between diabetic and non-diabetic patients. N significantly increased noradrenaline concentrations in plasma of hypertensive patients with or without DM. The data also demonstrated that the plasma concentrations of noradrenaline 30 min after N administration were lower (p<0.05) in diabetic (2.4 pmol.ml-1) than in non-diabetic patients (5.3 pmol.ml-1). The present data permit us to infer that type-2 diabetes mellitus alters the kinetic disposition of the (+)-N eutomer and (-)-N distomer due to the inhibition of CYP3A4, although it does not modify the clinical effect brought about by the reduction in BP. (AU)