Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus

• Published in: European journal of clinical pharmacology Vol. 58; no. 9; pp. 607 - 614
• Main Authors: MARQUES, Maria Paula, BARBOSA COELHO, Eduardo, GUINAIM DOS SANTOS, Neife Aparecida, MAGALHAES GELEILETE, Tufik José, LANCHOTE, Vera Lucia
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.12.2002; Berlin Springer Nature B.V
• Subjects: Adult; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Antihypertensive Agents - therapeutic use; Area Under Curve; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Biomarkers; Blood and lymphatic vessels; Blood Glucose - analysis; Blood Pressure - drug effects; Cardiology. Vascular system; Clinical manifestations. Epidemiology. Investigative techniques. Etiology; Cross-Over Studies; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - metabolism; Delayed-Action Preparations; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - metabolism; Female; Heart Rate - drug effects; Humans; Hypertension - complications; Hypertension - drug therapy; Hypertension - metabolism; Lidocaine; Male; Medical sciences; Middle Aged; Nisoldipine - pharmacokinetics; Nisoldipine - pharmacology; Nisoldipine - therapeutic use; Norepinephrine - blood; Stereoisomerism; Endocrinopathy; Cytochrome; Human; Hypertension; Nisoldipine; Diabetes mellitus; Calcium antagonist; Biological marker; Cardiovascular disease; Exploration; Chemotherapy; Association; Enantiomer; Dihydropyridine derivatives; Diabetes; Pharmacokinetics
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-002-0528-4

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. 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. 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)). 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.