Pharmacokinetic studies on nicardipine hydrochloride, a new vasodilator, after repeated administration to rats, dogs and humans.

1. Various doses of [14C]nicardipine HCl were administered orally at different intervals for different periods to rats and dogs, and cumulative excretion, plasma concn. of unchanged drug, plasma clearance, tissue distribution, and AUC determined. 2. Plasma concn. in 12 patients with cerebrovascular disease receiving 20 mg three times per day for 28 (6 patients) or 365 days (6 patients) was determined on various days 1 h after the third dose. 3. In tissues of rats receiving 3 mg/kg/day for 21 days, distribution 1 h after administration on day 14 was 1.4-2.5 times higher than on day one; there was no statistical difference between day 14 and 21, suggesting that a steady state had been established within 14 days. 4. In rats receiving 3 mg/kg/day for seven days, cumulative excretion was 97.3% administered drug, indicating no tendency to accumulation. 5. Doses of 10 mg/kg three times at 3 h intervals to dogs significantly increased the plasma concn. on repeated administration, but this was not the case if the drug was administered at 6 h intervals or if the dose was decreased to 2 mg/kg. These non-linear pharmacokinetics may be ascribable to saturation of the hepatic drug-metabolizing enzyme activity. 6. In dogs given 5 mg/kg three times per day at 3 h intervals for seven days, max. plasma concn. and AUC on day 4 were 1.8 and 1.6 times higher, respectively, than on day 1. On days 4 and 7, these values were similar, suggesting that a steady state had been established within 4 days. 7. In six patients receiving the drug for 28 days, the mean plasma concn. on day 1, 7, 14, and 28 was approx. 0.1 microgram/ml, similar to the value on day 365 in the other six patients. This indicates that during long periods of administration, the plasma concn. of the drug shows no tendency to increase.