The use of single sample clearance estimates to probe hepatic drug metabolism in rats. II

Abstract

1. Single sample clearance estimates, Čl, were calculated for each of five drugs employed as probes of hepatic drug-metabolizing activity in rats. Probe drugs were theophylline, phenytoin, valproic acid, antipyrine, and S-warfarin. Čl values were calculated for each probe in animals pretreated with phenobarbital, isosafrole, β-naphthoflavone, or clofibrate. Control animals were pretreated with vehicle only.

2. A clearance index (c.i., probe Čl after pretreatment divided by probe Čl control) was calculated for each probe and each pretreatment regimen, and data were consolidated to give different probe-based handprints of the pretreatment effects.

3. S-Wartarin was the least specific probe as its c.i. was greater than 1˙0 subsequent to each pretreatment. Theophylline appeared to be the most selective probe since its c.i. deviated significantly from unity (3˙56) only after β-naphthoflavone pretreatment. Phenytoin exhibited c.i. values less than unity after each pretreatment indicating that it may not, when used as a single sample probe of hepatic drug-metabolizing activity, effectively discriminate between inductive or inhibitory effects of xenobiotics.

4. Multi-probe-based handprints of hepatic drug-metabolizing activity structured from simple single sample estimates of probe clearance have potential in the rapid screening of xenobiotic-induced alterations of drug-metabolizing enzyme activity.