DISCREPANCIES IN PHARMACOKINETIC PARAMETER-ESTIMATION BETWEEN BOLUS AND INFUSION STUDIES IN THE PERFUSED RAT HINDLIMB

Isolated perfused rat hindlimb consists of skeletal muscle, skin, bone , and adipose. Hence, it is a heterogeneous preparation composed of sl owly equilibrating tissues of different characteristics and fractional flow rates. This paper shows how caution should be exercised in inter preting the results following bolus administration and subsequent stat istical moment analysis of intravascular markers (Cr-51-erythrocytes a nd I-125-albumin) and lipophilic harbiturates. For the intravascular m arkers, the events in the hindlimb are overshadowed by events in the c onnecting tubing and cannulas, due to their comparable volumes. For th e barbiturates, these estimates appear to apply to short-term effects as the volume estimates obtained following infusion to steady, state a re greater than after bolus administration. For the extravascular mark ers, C-14-sucrose, C-14-urea, and H-3-water, no such time dependency w as shown. However, it is only from the outflow profiles following bolu s administration that events in the tissue beds carl be elucidated.