The behaviour of doramectin in the gastrointestinal tract, its secretion in bile and pharmacokinetic disposition in the peripheral circulation after oral and intravenous administration to sheep.

Abstract

Sheep were 'compartmentalized' by surgically implanting cannulae in the rumen, abomasum and terminal ileum with a re-entrant cannula inserted between the cystic duct and the duodenum to monitor bile secretion. Doramectin, containing a trace of [3H]-doramectin, was administered both intravenously (i.v.) and intraruminally (i.r.) at a dosage of 150 microg/kg. The pharmacokinetic behaviour of [3H]-labelled products was determined in these pools, and also in peripheral plasma, urine and faeces. Parent doramectin was also determined in plasma, abomasal digesta fluid and bile. Following i.r. administration, [3H] compounds were almost entirely associated with particulate digesta. A 14.5 h half-life in the rumen prolonged the presence of [3H] in the abomasum. Doramectin appeared to be degraded in abomasal digesta because only 24% of abomasal [3H] was attributed to the parent drug. Absorption of doramectin resulted in a systemic availability of 35%, of which 1.6 and 23.6% of the dose was contained in urine and biliary secretions, respectively. Following i.v. administration, almost negligible quantities of [3H] were secreted into the rumen or abomasum and only 2.7% of the dose was excreted in urine, whereas 132% was secreted in bile. This indicated that approximately one-third of biliary metabolites were enterohepatically recycled with biliary metabolites, elevating the proportion of [3H] in fluid digesta in the small intestine. Passage of the i.r.-administered drug through the gastrointestinal tract (GIT) resulted in virtually complete faecal excretion of [3H] within 5 days, whereas the continued secretion of i.v.-administered [3H] in bile prolonged the presence of [3H] in the GIT, with faecal clearance not being complete for at least 10 days. This multi-compartmental study has provided more information on the behaviour of doramectin than can be obtained from examining drug disposition in the peripheral circulation alone. With this knowledge, it is anticipated that opportunities for improving drug performance will be identified.