Introduction
Recently, the pharmacokinetics of timolol, a padrenergic blocking agent and a propranolol analog, were reported for normal volunteers and uremic patients after oral administration. Clinically, timolol is more potent when compared to propranolol and alprenolol as an antihypertensive agent based on equal doses. I -A 20 mg dose per day given orally has resulted in an average plasma level of 50 ng mi-I, sufficient to control uncomplicated essential hypertension in patients with normal renal function. Similar plasma levels were achieved after 160-480 mg oral doses of propranolo14 and 200 mg of alprenolol.
This communication reports a method for calculating the systemic bioavailability, F, of timolol following oral doses without introducing blood level data obtained after intravenous administration of the drug. The calculated F values were compared with the reported values for propranolol and alprenolol, in an effort to explain the observed differences in the oral doses required to achieve approximately the same plasma levels and therapeutic responses. The first pass phenomenon may be the major factor accounting for the observed bioavailability differences. THEORETICAL Predictions of F value, the .fraction of the oral dose actually available to the systemic circulation, have been calculated using an equation derived from pharmacokinetic compartmental models. A more realistic approach was described by Rowland6 and Nies et al.;' these authors have applied the perfusion limited model where the main biological determinants of drug disposition such as the blood flow rate to the liver, the enzyme systems in the liver and the drug protein binding, were considered in the derivation of the final equation for