PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTIONS DURING MULTIPLE-DOSEADMINISTRATION OF NISOLDIPINE AND PROPRANOLOL

Objectives: The pharmacokinetic and pharmacodynamic interactions after 7 days of oral treatment with nisoldipine (10 mg twice daily) and pro pranolol (80 mg twice daily) were investigated in a partially randomiz ed, placebo-controlled crossover study of 12 healthy volunteers. Metho ds: At the end of each treatment period, pharmacokinetic parameters we re measured, along with blood pressure, heart rate, cardiac function, systemic hemodynamics, plasma catecholamines, forearm blood flow, and apparent hepatic blood flow (estimated by the clearance of indocyanine green dye). Results: After 7 days of treatment with nisoldipine and p ropranolol, neither drug altered the other's bioavailability or elimin ation parameters, and propranolol did not change the area under the pl asma concentration-time curve of nisoldipine's metabolite, N-9425. Nis oldipine alone increased apparent hepatic blood flow and forearm blood flow compared with the other treatment groups but, with the addition of propranolol, both of these parameters were similar to those in the placebo group. Changes in the other hemodynamic parameters were consis tent with the known effects of these drugs, and no differences in plas ma catecholamine levels were detected. Conclusions: In contrast to the findings with single-dose treatment, administration of the combinatio n of nisoldipine and propranolol for 7 days is not associated with any measurable kinetic interactions, although significant hemodynamic int eractions do occur.