1. Conditions were examined under which estimates of drug clearance made from a single measurement of plasma concentration effectively represented multisample estimates of clearance. When plasma concentrations were measured at various post-dose times, both individual and mean values of single sample clearance estimates, Cl, corresponded closely to multisample clearance estimates, Cl, and significant differences between Cl and Cl could not be detected. 2. Best post-dose sampling times were: theophylline, 6 h; phenytoin, 2 h; valproic acid, 20 min; antipyrine, 4 h; and S-warfarin, 48 h. 3. When theophylline clearance was evaluated by both multisample and single sample experiments during diethyl ether versus urethane anaesthesia, clearances were about 50% slower for ether-anaesthetized rats. This outcome was qualitatively and quantitatively the same regardless of whether single sample or multiple sample clearances were estimated, and single sample theophylline clearances were virtually identical to multisample clearances under both anaesthetic conditions. 4. We conclude that multiple drugs can be potentially useful for probing hepatic drug metabolizing activity in rats when using a single plasma measurement to estimate clearance. An appropriate array of such probes might effectively be used to handprint host-factor influences on drug metabolizing activity.