Pharmacokinetic interactions of timolol with vasodilating drugs, food and phenobarbitone in healthy human volunteers.

Pharmacokinetic interactions of oral timolol maleate 10 mg, with food (3566 kJ), single oral doses of prazosin 1 mg and dihydralazine 25 mg, and with a 1 week pretreatment with phenobarbitone 100 mg daily were examined in a randomized crossover study in 12 healthy volunteers. After fasting, the peak level (Cmax = 29.1 +/- 3.2 ng/ml; mean +/- SEM) was reached at 1.3 +/- 0.1 h (Tmax). The total area under the serum concentration-time curve (AUC0-infinity) was 154.4 +/- 33.8 ng x h/ml, total clearance (Cltot) 751.5 +/- 90.6 ml/min, renal clearance (Clren) 97.2 +/- 10.1 ml/min, elimination half-life (t1/2) 2.9 +/- 0.3 h and 24-h recovery in urine (X0u-24) 11.1 +/- 1.4% of the dose. Food and prazosin did not significantly affect the fate of timolol maleate. Dihydralazine enhanced Cmax (38.2 +/- 4.6 ng/ml) only when compared to phenobarbitone treatment, and did not affect any other parameters. Phenobarbitone pretreatment somewhat lowered Cmax (25.5 +/- 3.9 ng/ml), AUC0-infinity (117.5 +/- 22.1; p less than 0.05 vs food) and X0u-24 (8.7 +/- 1.2%), evidently by increasing Cltot (957.5 +/- 116.9 ml/min; p less than 0.05 vs food), but it did not affect Clren. It is concluded that the pharmacokinetics of timolol maleate can be altered to a limited extent in opposite directions by dihydralazine and phenobarbitone.