Chronopharmacological Study of Nitrendipine in Healthy Subjects

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Abstract
Nitrendipine 20 mg or placebo was given orally to eight healthy subjects in a cross‐over design separated by 1 or 2 weeks. Drug was given at 9:00 AM (morning dosage) or at 9:00 PM (evening dosage). Systolic and diastolic blood pressure (SBP, DBP) were measured just before and 1, 2, 3, 4, 5, 7, 9, 12 and 24 hrs after treatment. Plasma nitrendipine concentrations were determined at 0.5, 1, 2, 3, 4, 5, 7, 9, 12 and 24 hrs and plasma catecholamines were measured at 2 and 5 hrs following drug administration. SBP did not decrease significantly after nitrendipine compared to after placebo at 9:00 AM or at 9:00 PM. DBP decreased significantly at 2, 3, 4 and 5 hrs after nitrendipine at 9:00 AM, but only at 4 hours after the 9:00 PM dose. Mean plasma nitrendipine concentrations during the absorption phase were lower after the evening dosage compared to the morning interval. Maximum plasma concentration (Cmax) was significantly lower and time to maximum concentration (tmax) tended to be longer after the evening dosage. Area under the plasma concentration‐time curve from 0 to 24 hours (AUC0–24) and half‐life of the terminal elimination phase (t1/2β) of the morning and evening dosages did not differ. A significant correlation was observed between plasma nitrendipine concentrations and changes in DBP during the drug treatment. Plasma noradrenaline concentrations were significantly higher 5 hours after nitrendipine compared to after placebo at 9:00 AM, but not at 9:00 PM. These results suggest 1) that BP responsiveness to nitrendipine is relatively smaller after the evening dosage when compared to after the morning dosage, 2) that nitrendipine is absorbed more slowly from the gastrointestinal tract after the evening dosage than after the morning dosage, and 3) that the diurnal changes in the effects of nitrendipine are in part dependent on the time of administration and its subsequent effect on plasma concentrations of the drug.