Abstract

The effects of varying flow from 5-20 ml/min on the elimination of propranolol by the perfused rat liver have been investigated. Both d- and dl-propranolol were handled similarly at all flows and doses employed. By using two doses (1 and 5 mg in a 100-ml reservoir) the effects of flow under three distinct kinetic conditions could be examined. At the low dose and during the α-phase with the high dose, disposition was entirely flow-dependent as drug clearance equalled liver blood flow. During the β-phase following the high dose, clearance was less and increased with flow until a limiting value was achieved when drug clearance was independent of flow. The effects of flow on total clearance of the high dose (including α- and β-phases) were intermediate. Theoretical analysis of the data shows that drug clearance should increase with flow until a limiting value is reached corresponding to the intrinsic first-order metabolic clearance of the drug, when elimination becomes flow-independent. As a result, hepatic extraction ratio decreases as flow increases in relation to metabolic clearance rate despite metabolism remaining first order. These data 1) suggest that the effect of flow on the clearance of any drug can be assessed from a single estimate of flow and extraction ratio and 2) quantitate the observation that the elimination of high-clearance drugs is more affected by flow changes than that of low-clearance drugs.