Kinetics of Drug Action in Disease States. XLIII: Potentiating Effect of l-Tryptophan on the Hypnotic Action of Phenobarbital and Ethanol in Rats

Abstract

The essential amino acidl-tryptophan has been widely used as a sleeping aid because it can produce drowsiness and decrease sleep latency. Its concentrations in plasma and brain and its binding to plasma protein are markedly altered in hepatic encephalopathy and renal failure. The purpose of this investigation was to determine ifl-tryptophan can enhance the sensitivity of the central nervous system to the hypnotic actions of a barbiturate and an alcohol. Female rats weighing ∼200 g received an intravenous infusion ofl-tryptophan (0.8 or 0.08 mg/min) for 30 min and then an infusion of phenobarbital (0.824 mg/min) withl-tryptophan (0.8 or 0.08 mg min−1) until the onset of loss of righting reflex (LRR). Control animals received an infusion of saline solution for 30 min and then phenobarbital without the amino acid. Similar experiments were performed with ethanol (16.3 mg/min), with and withoutl-tryptophan (0.8 mg/min).L-Tryptophan infused alone at a rate of 3.8 mg/min for 84 min did not cause LRR. Administration ofl-tryptophan at a rate of 0.8 mg/min with phenobarbital was associated with statistically significant reductions in the total dose and concentrations of phenobarbital in serum, serum water, brain, and cerebrospinal fluid (CSF) at onset of LRR. The 0.08 mg/min infusion ofl-tryptophan had a less pronounced effect, with statistically significant reductions of phenobarbital concentrations at onset of LRR in brain and CSF.L-Tryptophan also significantly reduced the total dose and the concentrations of ethanol in serum, brain, and CSF required to produce LRR. It is concluded thatl-tryptophan can potentiate the central nervous system depressant effects of phenobarbital and ethanol.