No abstract

1. Single and multiple dose disposition kinetics of ethosuximide were studied in male Sprague-Dawley rats following intravenous administration. 2. The plasma disappearance of a single 35 mg/kg dose followed for 75 h was not linear. A dose-ranging study suggested that the apparent non-linearity of ethosuximide's plasma disappearance might be due to enzyme induction over time with the drug exhibiting a faster elimination from 24 h onward. 3. Ethosuximide, after only two daily doses of 35 mg/kg/day, shortened pentobarbital-induced sleep in rats. The clearance of ethosuximide was also significantly faster after four daily 35 mg/kg doses than after a single 35 mg/kg dose. 4. Single sample clearance estimates calculated from ethosuximide concentrations prior to enzyme induction, viz. up to 24 h post-dose, were practically identical to multiple sample clearance values. Both single and multiple sample clearances were calculated assuming linear rather than non-linear elimination.

1. Single sample clearance estimates, Cl, 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. Cl values were calculated for each probe in animals pretreated with phenobarbital, isosafrole, beta-naphthoflavone, or clofibrate. Control animals were pretreated with vehicle only. 2. A clearance index (c.i., probe Cl after pretreatment divided by probe Cl 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-Warfarin 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 beta-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.

We study the interplay between the discrete geometry of Bruhat poset intervals and subword complexes of finite Coxeter systems. We establish connections between the cones generated by cover labels for Bruhat intervals and of root configurations for subword complexes, culminating in the notion of brick polyhedra for general subword complexes.

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.