Disposition of SK&F L-190144 in rats and monkeys after oral, intravenous or ocular administration

The objective of the study was to investigate the systemic disposition of 14C-SK&F L-190144 after single intravenous (10 mg kg-1) and oral (200 mg kg-1) doses to rats and after single intravenous and ocular doses (0.33 mg kg-1) to monkeys. After the intravenous dose, the blood concentration-time profile of 14C-SK&F L-190144 followed a rapid triexponential decline with half-lives of 2.5, 15, and 246 min in rats and 3, 19, and 2520 min in monkeys. The 14C-label in blood was mainly the parent compound. The terminal elimination half-life detected in rats using the urinary excretion rate-time data was 700 min. The total body clearance values were 17.6 +/- 2.1 (mean +/- SD, n = 6) and 1.11 +/- 0.41 (n = 4) ml min-1 kg-1 for rats and monkeys, respectively. Both species had similar values of volume of distribution at the terminal phase, 4 to 6 l kg-1, and similar excretion patterns, approximately 60 per cent and 30 per cent of the dose were excreted in the urine and feces, respectively. 14C-SK&F L-190144 was not absorbed orally in rats with the majority of the dose recovered in the feces. Following ocular administration to monkeys, the plasma drug concentrations peaked at 8 h post-dosing but did not reach a biexponential elimination phase until 18 h post-dosing, suggesting slow systemic absorption of drug from the ocular site. The monkeys excreted 42 per cent of the dose in urine and 50 per cent in feces after ocular administration. This increase in fecal excretion compared to the intravenous route of administration may have been due to the slow absorption by the ocular and nasal tissues altering the relative proportions of drug elimination via the renal and hepatic routes, or to a proportion of the dose passing into the gastrointestinal tract and exiting unabsorbed. Study results demonstrate similar excretion patterns and volume of distribution after intravenous administration in both species. The slow terminal elimination phase in monkeys was attributed to the low body clearance. The low oral bioavailability was possibly due to the poor partitioning behavior of the drug (logarithm of partition coefficient -2.6). A significant fraction of the dose was absorbed in the body via the ocular route.