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.

Relationship between baseline blood pressure and blood pressure decrease after calcium channel blockers in conscious rats.

OBJECTIVE: To determine whether vasodilators produce a fall in mean blood pressure (MBP) that is directly proportional to baseline MBP. DESIGN: The effects on blood pressure of three calcium channel blockers, nitrendipine, nisoldipine and verapamil, were compared with sodium nitroprusside, a drug acting through a different mechanism. The drugs were infused in conscious, unrestrained rats and their effect on MBP was measured. SETTING: Primary experimental. ANIMALS: Animals were divided into three groups according to their baseline MBP: high (greater than 119 mmHg), moderate (91 to 119 mmHg) and normal (less than 91 mmHg). INTERVENTIONS: Five successive infusion rates for each drug were tested in each animal. MBP readings were taken at the end of each infusion period (usually 10 mins). MAIN RESULTS: At the maximal dose infused, nitrendipine (0.57 mg/kg.min) lowered MBP 13 +/- 6 mmHg in the low MBP rats, 51 +/- 4 mmHg in the rats with moderate MBP and 83 +/- 8 mmHg in the rats with high MBP (P < 0.05 within groups). Similar results (ie, the greater the baseline MBP, the greater the fall in MBP) were obtained with nisoldipine and verapamil. In the same groups, sodium nitroprusside (0.096 mg/kg.min) produced a fall of 52 +/- 3 mmHg, 56 +/- 5 mmHg and 54 +/- 13 mmHg, respectively (not significant). CONCLUSIONS: Nitrendipine, nisoldipine and verapamil behave as antihypertensives since their effect increased as a function of the initial MBP, while sodium nitroprusside showed no effect related to baseline MBP.