Pharmacokinetics and CNS pharmacodynamics of the 5-HT1A agonist buspirone in humans following acute L-tryptophan depletion challenge.

This study was designed to evaluate the relationship between the pharmacokinetic(s) (PK) and CNS pharmacodynamic(s) (PD) of buspirone, an antidepressant/anxiolytic, in 6 healthy male volunteers placed on an acute L-tryptophan deficient (ATD) diet. The study was a randomized, double-blind, placebo-controlled, four-period, three-way crossover study. The first study period was a single-blind familiarization period in which all subjects received placebo. During the remaining three study periods, subjects received either placebo, 10 mg or 30 mg oral buspirone. Subjects were administered the ATD diets 5 h prior to buspirone/placebo administration during each study period. All subjects underwent serial measurements of resting electroencephalography (REEG) and vigilance electroence-phalography (VEEG), cognitive tests, subjective rating scales, and blood was sampled for determination of unbound plasma L-tryptophan, serum prolactin, serum cortisol and plasma buspirone and its active metabolite, 1-pyrimdylpiperazine (1-PP). The ATD diet reduced the unbound plasma L-tryptophan concentrations to 20% of their baseline values. The intraindividual and interindividual variability in the unbound L-tryptophan concentration drop was less than 10% and 15%, respectively. Peak L-tryptophan depletion occurred 5 h after ATD diet was administered; L-tryptophan depletion lasted for approximately 11 h, and L-tryptophan concentrations recovered to baseline values approximately 13 h after administration of the ATD diet. PK-PD analysis for buspirone showed that: 1) peak plasma concentration (Cmax) and total area under the plasma concentration-time curve (AUC infinity) for buspirone following the 10 mg dose in this study were higher than those reported previously in the literature; 2) there was a transient response in the neuroendocrine measures, subjective rating scales and the EEG, but no changes in the cognitive tests with increasing doses of buspirone; 3) the PD measures were correlated with the doses of buspirone, but not with plasma concentrations of buspirone and 1-PP; and 4) the subjective rating scales were the most sensitive indicators of buspirone's CNS effects. This study provides evidence that ATD diet is a simple, specific and non-toxic experimental method to lower plasma L-tryptophan concentrations and thereby (indirectly) deplete brain tryptophan and serotonin (5-HT) concentrations. The ATD challenge may serve as a model of depression in healthy volunteers because of its ability to induce transient symptoms of the disease. Comparison of the results from this study to those reported in the literature suggests that the use of the ATD diet decreases the buspirone-induced neuroendocrine response, increases the buspirone-induced changes in subjective rating scales and, at the same time, increases the systemic exposure to buspirone and 1-PP.