Kinetics of drug action in disease states. II. Effect of experimental renal dysfunction on phenobarbital concentrations in rats at onset of loss of righting reflect.
The purpose of this investigation was to determine if renal dysfunction is associated with an alteration in the concentration-pharmacologic activity relationship of phenobarbital (PB). Adult female rats (congruent to 200 g) were pretreated with uranyl nitate or subjected to bilateral ureteral ligation to produce renal dysfunction. Saline-injected and sham-operated rats, respectively, served as controls. PB (0.824 mg/min) was infused i.v. until the animals lost their righting reflex (LRR). Renal dysfunction reduced the total dose of PB required to produce LRR, the concentrations of total and free (unbound) PB in serum and the concentrations of PB in brain and cerebrospinal fluid at onset of LRR. Results were quantitatively similar in both experimental models of impaired renal function. Concomitant infusion of p-hydroxyphenobarbital (the major metabolite of PB) and PB in rats with uranyl nitrate-induced renal dysfunction had no effect on the PB concentrations at onset of LRR. When PB was infused at different rates (either 0.412, 0.824, 2.04 or 4.12 mg/min), rats with renal dysfunction had increasing concentrations of PB at onset of LRR with increasing infusion rate, not only in serum and brain but also (unlike normal rats) in cerebrospinal fluid. Thus, renal dysfunction is associated with increased sensitivity to PB and with a change in the kinetic relationship between PB in cerebrospinal fluid and in the biophase.
D058186:Acute Kidney Injury / Q000134:cerebrospinal fluid* / Q000139:chemically induced; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007700:Kinetics; D010634:Phenobarbital / Q000031:analogs & derivatives / Q000134:cerebrospinal fluid* / Q000494:pharmacology; D011187:Posture; D051381:Rats; D011917:Rats, Inbred Lew; D012018:Reflex / Q000187:drug effects*; D014502:Uranyl Nitrate
D014502:Uranyl Nitrate; C017414:4-hydroxyphenobarbital; D010634:Phenobarbital