Dynamic and kinetic disposition of nisoldipine enantiomers in hypertensive patients presenting with type-2 diabetes mellitus.
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.
Marques
Maria Paula
MP
Faculdade de Ciências Farmacêuticas, Universidade São Paulo, Brazil.
Coelho
Eduardo Barbosa
EB
Dos Santos
Neife Aparecida Guinaim
NA
Geleilete
Tufik José Magalhães
TJ
Lanchote
Vera Lucia
VL
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
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