title: Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus.
abstract: 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): 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.
authors.affiliation: Faculdade de Ciências Farmacêuticas, Universidade São Paulo, Brazil.
authors.forename: Maria Paula
authors.initials: MP
authors.lastname: Marques
authors.forename: Eduardo Barbosa
authors.initials: EB
authors.lastname: Coelho
authors.forename: Neife Aparecida Guinaim
authors.initials: NA
authors.lastname: Dos Santos
authors.forename: Tufik José Magalhães
authors.initials: TJ
authors.lastname: Geleilete
authors.forename: Vera Lucia
authors.initials: VL
authors.lastname: Lanchote
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D019540:Area Under Curve; D015415:Biomarkers; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D018592:Cross-Over Studies; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003692:Delayed-Action Preparations; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D015737:Nisoldipine / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D009638:Norepinephrine / Q000097:blood; D013237:Stereoisomerism
chemical_list: D000959:Antihypertensive Agents; D015415:Biomarkers; D001786:Blood Glucose; D003692:Delayed-Action Preparations; D015737:Nisoldipine; D003577:Cytochrome P-450 Enzyme System; D008012:Lidocaine; C104464:CYP3A protein, human; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009638:Norepinephrine