A SHEEP PREPARATION FOR STUDYING INTERACTIONS BETWEEN BLOOD-FLOW AND DRUG DISPOSITION .1. PHYSIOLOGICAL PROFILE

Patients undergoing anesthesia, surgery and intensive care may suffer profound changes in physiological processes such as tissue O2 delivery and organ blood flow. Most of these patients receive drugs, some of which may have low therapeutic indices even under physiological conditions. Drug disposition may be altered and may lead to unpredicted, exaggerated or toxic drug responses. A sheep preparation was developed which allows repeated measurements of regional blood flow, O2 consumption and drug disposition in awake, unrestrained animals. This allows systematic studies of both acute changes, such as hemodynamic disturbances, and of chronic changes, such as enzyme induction, to be carried out. Good agreement was shown between the values for cardiac output and regional blood flow obtained by the Fick and indicator dilution methods, and those obtained by others using microspheres. Significant day-to-day fluctuations in hemodynamic indices occurred. Assumptions that hepatic or renal blood flows are constant fractions of cardiac output, or that renal or hepatic flow indicator extraction ratios remain unchanged from day-to-day, will lead to significant errors. Control measurements for each experiment are necessary. Physiological models for studying drug disposition based on data from awake, unrestrained animals may provide insight into some mechanisms of changes in drug disposition that cannot be obtained using the traditional compartmental method.