Urinary metabolites of timolol from humans and laboratory animals. Syntheses and beta-adrenergic blocking activities.

Syntheses are reported for three metabolites (2-4) of timolol (1) formed by oxidative metabolism of the morpholine ring. GLC-MS comparisons are presented which establish that the two metabolites whose structures were previously in question are identical with their synthetic counterparts 2 and 3. In 2, metabolic oxidation of the 4-morpholinyl group of 1 had occurred at the carbon next to oxygen to give the 2-hydroxy-4-morpholinyl moiety, whereas in 3, the morpholine of 1 has been oxidized one step further and then ring opened to produce the N-(2-hydroxyethyl)glycine substituent. Biological testing of synthetic samples of the three major metabolites from human urine (3, 4, and 6) indicated that only 4, in which the morpholine moiety has been degraded to a 2-hydroxyethylamino group, had significant beta-adrenergic blocking activity (one-seventh that of timolol in anesthetized dogs).

Physiological disposition of alendronate, a potent anti-osteolytic bisphosphonate, in laboratory animals.

Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonate) is currently under investigation as an anti-osteolytic agent in the treatment of a broad range of bone disorders. This study describes the absorption and disposition of the drug in laboratory animals. Following iv administration, alendronate was rapidly cleared from plasma, either taken up and sequestered in the bone or excreted by the kidney. About 30 to 40% of the dose was excreted in the urine in 24 hr, with most of the drug being excreted in the first 3 to 4 hr. There was little or no accumulation of the drug in noncalcified tissues and only a very small fraction of the dose was excreted in the bile. Most of the dose was rapidly taken up by bone tissues: 30% in 5 min, 60% in 1 hr. Absorption of alendronate was very poor. Based on the ratios in bone of the labels from the 14C-labeled oral dose and the 3H-labeled iv dose, absorption was estimated to be about 0.9% for the rat, 1.8% for the dog, and 1.7% for the monkey. Comparison of the concentrations of alendronate in bones of the same rats in fasted (3H-labeled) and fed (14C-labeled) states indicated that food caused a substantial decrease in absorption, by about 6- to 7-fold. The terminal half-life of alendronate in bone was about 200 days for the rat. Based on urinary excretion, the terminal half-life was estimated to be about 1000 days for the dog. The long persistence of alendronate in bone was likely due to its slow dissolution rate from bone tissues.