Jagannathan V, Venitz J
Department of Pharmacy and Pharmaceutics, Virginia Commonwealth University, Richmond, USA.
Methods Find Exp Clin Pharmacol. 1997 Jun;19(5):351-62.
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.
本研究旨在评估抗抑郁/抗焦虑药物丁螺环酮的药代动力学（PK）与中枢神经系统药效学（PD）之间的关系，研究对象为6名健康男性志愿者，他们采用急性L-色氨酸缺乏（ATD）饮食。该研究是一项随机、双盲、安慰剂对照、四期、三交叉试验。第一个研究期为单盲熟悉期，所有受试者均接受安慰剂。在其余三个研究期内，受试者分别接受安慰剂、10mg或30mg口服丁螺环酮。在每个研究期内，受试者在服用丁螺环酮/安慰剂前5小时接受ATD饮食。所有受试者均接受静息脑电图（REEG）和警觉脑电图（VEEG）的连续测量、认知测试、主观评分量表，并采集血样以测定游离血浆L-色氨酸、血清催乳素、血清皮质醇以及血浆丁螺环酮及其活性代谢物1-嘧啶基哌嗪（1-PP）。ATD饮食将游离血浆L-色氨酸浓度降至基线值的20%。游离L-色氨酸浓度下降的个体内和个体间变异性分别小于10%和15%。ATD饮食给药后5小时出现L-色氨酸峰值耗竭；L-色氨酸耗竭持续约11小时，ATD饮食给药后约13小时L-色氨酸浓度恢复至基线值。丁螺环酮的PK-PD分析表明：1）本研究中10mg剂量丁螺环酮后的血浆峰值浓度（Cmax）和血浆浓度-时间曲线下总面积（AUC∞）高于先前文献报道的值；2）随着丁螺环酮剂量增加，神经内分泌指标、主观评分量表和脑电图出现短暂反应，但认知测试无变化；3）药效学指标与丁螺环酮剂量相关，但与丁螺环酮和1-PP的血浆浓度无关；4）主观评分量表是丁螺环酮中枢神经系统效应最敏感的指标。本研究提供的证据表明，ATD饮食是一种简单、特异且无毒的实验方法，可降低血浆L-色氨酸浓度，从而（间接）耗尽脑内色氨酸和5-羟色胺（5-HT）浓度。ATD激发试验可作为健康志愿者抑郁症的模型，因为它能够诱发该疾病的短暂症状。将本研究结果与文献报道结果进行比较表明，使用ATD饮食可降低丁螺环酮诱导的神经内分泌反应，增加丁螺环酮诱导的主观评分量表变化，同时增加丁螺环酮和1-PP的全身暴露量。
