A SHEEP PREPARATION FOR STUDYING INTERACTIONS BETWEEN BLOOD FLOW AND DRDRUG DISPOSITION.

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Abstract
Blood flow through and pethidine extraction ratios across lungs, liver, kidneys and the gastrointestinal tract were measured in awake unrestrained sheep (controls) and with the animals anaesthetized with 1.5% halothane or whilst undergoing high thoracic subarachnoid block with amethocaine. In the control studies, pethidine infused to several times the blood concentrations required for postoperative analgesia in man produced no significant changes in haemodynamics or in the kinetics of iodohippurate (renal and hepatic blood flow); pethidine hepatic extraction ratios were consistently greater than 0.97; renal extraction ratios ranged from negligible to 0.30; and there was negligible extraction across the lungs and the gastrointestinal tract. Under general anaesthesia there were significant reductions in mean cardiac output (46%), mean hepatic blood flow (46%), mean renal blood flow (55%), mean arterial pressure (30%) and mean iodohippurate clearance (17%); but mean arterial blood concentrations of pethidine were doubled, mean hepatic clearance of pethidine was reduced to 60% of control and renal clearance was virtually abolished. With subarachnoid anaesthesia there were not significant changes in haemodynamics or in pethidine or iodohippurate extraction ratios or clearances. Summed measured regional clearances accounted for only one- to two-thirds of the total body clearance of pethidine; the rest was by extravisceral clearance or high affinity tissue binding.

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