Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York, 14214, USA.
Preclinical and Translational Pharmacokinetics and Pharmacodynamics (PTPK), Genentech Inc., South San Francisco, California, USA.
AAPS J. 2017 Sep;19(5):1449-1460. doi: 10.1208/s12248-017-0111-7. Epub 2017 Jun 26.
An overdose of γ-hydroxybutyric acid (GHB), a drug of abuse, results in fatality caused by severe respiratory depression. In this study, a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to characterize monocarboxylate transporter 1 (MCT1)-mediated transport of GHB, as well as effects of GHB on respiration frequency, for IV doses of 200, 600, and 1500 mg/kg in rats. The proposed PK/PD model for GHB consists of nonlinear metabolism of GHB in the liver, MCT1-mediated renal reabsorption with physiologically relevant concurrent fluid reabsorption, MCT1-mediated uptake into the brain, and direct effects of binding of GHB to GABA receptors on the PD parameter, respiration frequency. Michaelis-Menten affinity constants for metabolism, renal reabsorption, and uptake into and efflux from the brain were fixed to the observed in vitro values. The IC value for the effect of GHB on respiration frequency was fixed to a reported value for binding of GHB to GABA receptors. All physiological parameters were fixed to the reported values for a 300-g rat. The model successfully captured the GHB PK/PD data and was further validated using the data for a 600-mg/kg dose of GHB after IV bolus administration. Unbound GHB brain ECF/blood partition coefficient (Kp ) values obtained from the model agreed well with values calculated using experimental ECF concentrations obtained with brain microdialysis, demonstrating the physiological relevance of this model. Sensitivity analysis indicated that the PK/PD model was stable. In conclusion, we developed a semi-mechanistic and physiologically relevant PK/PD model of GHB using in vitro drug-transporter kinetics and in vivo PK/PD data in rats.
γ-羟基丁酸（GHB）是一种滥用药物，过量使用会导致严重的呼吸抑制而致命。在这项研究中，建立了一个半机械的药代动力学/药效动力学（PK/PD）模型，以描述 GHB 经单羧酸转运蛋白 1（MCT1）介导的转运，以及 GHB 对呼吸频率的影响，该模型用于研究大鼠静脉注射 200、600 和 1500mg/kg 剂量的 GHB。GHB 的 PK/PD 模型由肝脏中 GHB 的非线性代谢、MCT1 介导的肾脏重吸收（伴有生理相关的伴随液体重吸收）、MCT1 介导的脑摄取以及 GHB 与 GABA 受体结合对 PD 参数（呼吸频率）的直接作用组成。代谢、肾脏重吸收以及脑内摄取和流出的米氏常数亲和力常数固定为观察到的体外值。GHB 对呼吸频率影响的 IC50 值固定为报告的 GHB 与 GABA 受体结合的数值。所有生理参数均固定为 300 克大鼠的报告值。该模型成功地捕获了 GHB 的 PK/PD 数据，并使用静脉推注 600mg/kg 剂量的 GHB 后的 PD 数据进行了进一步验证。从模型中获得的未结合 GHB 脑细胞外液/血液分配系数（Kp）值与使用脑微透析获得的实验细胞外液浓度计算的值吻合良好，证明了该模型的生理相关性。敏感性分析表明 PK/PD 模型稳定。总之，我们使用体外药物转运体动力学和大鼠体内 PK/PD 数据，开发了一个半机械和生理相关的 GHB PK/PD 模型。
