THE EFFECT OF OXPRENOLOL DOSAGE TIME ON ITS PHARMACOKINETICS AND HEMODYNAMIC-EFFECTS DURING EXERCISE IN MAN

We have studied the effect of dosage time of oxprenolol (Trasicor(R)) on its pharmacokinetics and pharmacodynamics in six healthy volunteers. The drug effects measured were heart rate and systolic blood pressure during exercise. Oxprenolol was taken orally at 08.00 h, 14.00 h, 20.00 h, and 02.00 h in randomized order, with 1 week between successive doses. There were differences in the pharmacokinetics of oxprenolol for the ratio between the apparent volume of distribution and systemic availability (P = 0.04) and for elimination half-life (P = 0.006). Both were lowest after administration at 14.00 h (163 (77) 1 and 1.2 (0.6) h; mean (SD)) and highest after administration at 02.00 h (229 (100) 1, and 1.7 (0.6) h). The systolic blood pressure during exercise before oxprenolol did not vary with dosage time, but heart rate during exercise before intake was lowest before dosage time 08.00 h and highest before dosage time 20.00 h (P = 0.03). The time-course of heart rate during exercise after oxprenolol was described by a model that incorporated the factors drug concentration and spontaneous diurnal variation. EC50 and E(max) did not vary between dosage times. The spontaneous diurnal variation in heart rate during exercise was unaffected by oxprenolol, leading to an apparently greater effect of oxprenolol during the night than during the day.