Uptake of the beta-adrenergic blocking agents propranolol and timolol by rodent brain: relationship to central pharmacological actions.

Abstract

Summary Propranolol produces side effects of apparent central nervous system (CNS) origin in man, and this compound is active in animals in certain pharmacological tests measuring CNS activity. The purpose of the present investigation was to compare another β-blocker, timolol, with propranolol for CNS activity in mice and for their relative abilities to enter the whole brain of mice and rats. In mice at doses up to 243 mg/kg, i.p., timolol failed to block tonic hindlimb extension induced by electroshock, whereas propranolol protected with an ED50 of 17.8 mg/kg, i.p. Timolol antagonized head twitches in mice caused by DL-5-hydroxytryptophan with an ED50 about 17 times higher than propranolol. 3H-Propranolol accumulated in the brain in a dose-dependent manner after doses of 1, 5, and 10 mg/kg, p.o.; at 1 hr after dosing, rat brain had levels of 9, 59, and 306 ng equivalents/g, respectively. The brain/plasma concentration ratio ranged from 5.7 to 12.7. In contrast, the brain levels of 11C-timolol (shown to be a less lipid-soluble compound than propranolol) were only 1.5, 4.8, and 55.4 ng/g at 1 hr after the same doses. The brain/plasma concentration ratio ranged from 0.28 to 1.02. Similar differences in the concentration of propranolol and timolol in brain were observed in mice. 3H-Propranolol metabolites represent a substantial proportion of total drug residue in the brain. At 1 hr after 1, 5, or 10 mg/kg, p.o., rat brain had the following ng equivalents of propranolol: 148 ng/g, 629 ng/g, and 1,201 ng/g, respectively. The brain/plasma ratio was 0.38 to 0.48. In contrast, the ratio for timolol metabolites was 0.04 $pM 0.007, a value barely significantly higher than 11C-inulin (0.02 $pM 0.005), a compound which does not cross the blood-brain barrier. Metabolites of propranolol accumulated in the brain after multiple doses. Thus, rats given 5 mg/kg, p.o., at 24 hr intervals for 4 days showed a more than fivefold increase in brain levels. Propranolol, timolol, and timolol metabolites showed slight, and in most cases insignificant, changes in brain levels of these substances following multiple dosing.