Discrepancies in pharmacokinetic parameter estimation between bolus and infusion studies in the perfused rat hindlimb

Abstract

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