Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, 14214, USA.
Department of Pharmaceutics & Medicinal Chemistry, Thomas J Long School of Pharmacy & Health Sciences, University of the Pacific, Stockton, California, 95211, USA.
AAPS J. 2017 Dec 26;20(1):21. doi: 10.1208/s12248-017-0180-7.
The drug of abuse γ-hydroxybutyric acid (GHB) demonstrates complex toxicokinetics with dose-dependent metabolic and renal clearance. GHB is a substrate of monocarboxylate transporters (MCTs) which are responsible for the saturable renal reabsorption of GHB. MCT expression is observed in many tissues and therefore may impact the tissue distribution of GHB. The objective of the present study was to evaluate the tissue distribution kinetics of GHB at supratherapeutic doses. GHB (400, 600, and 800 mg/kg iv) or GHB 600 mg/kg plus L-lactate (330 mg/kg iv bolus followed by 121 mg/kg/h infusion) was administered to rats and blood and tissues were collected for up to 330 min post-dose. K values for GHB varied in both a tissue- and dose-dependent manner and were less than 0.5 (except in the kidney). Nonlinear partitioning was observed in the liver (0.06 at 400 mg/kg to 0.30 at 800 mg/kg), kidney (0.62 at 400 mg/kg to 0.98 at 800 mg/kg), and heart (0.15 at 400 mg/kg to 0.29 at 800 mg/kg), with K values increasing with dose consistent with saturation of transporter-mediated efflux. In contrast, lung partitioning decreased in a dose-dependent manner (0.43 at 400 mg/kg to 0.25 at 800 mg/kg) suggesting saturation of active uptake. L-lactate administration decreased K values in liver, striatum, and hippocampus and increased K values in lung and spleen. GHB demonstrates tissue-specific nonlinear distribution consistent with the involvement of monocarboxylate transporters. These observed complexities are likely due to the involvement of MCT1 and 4 with different affinities and directionality for GHB transport.
滥用药物 γ-羟基丁酸（GHB）具有复杂的毒代动力学特征，其代谢和肾清除率呈剂量依赖性。GHB 是单羧酸转运体（MCTs）的底物，负责 GHB 的饱和性肾重吸收。MCT 表达存在于许多组织中，因此可能会影响 GHB 的组织分布。本研究的目的是评估超治疗剂量下 GHB 的组织分布动力学。GHB（400、600 和 800mg/kg 静脉注射）或 GHB（600mg/kg 加 L-乳酸（330mg/kg 静脉推注，随后 121mg/kg/h 输注）分别给大鼠给药，并在给药后 330min 内采集血液和组织。GHB 的 K 值呈组织和剂量依赖性变化，均小于 0.5（肾脏除外）。在肝脏（400mg/kg 时为 0.06，800mg/kg 时为 0.30）、肾脏（400mg/kg 时为 0.62，800mg/kg 时为 0.98）和心脏（400mg/kg 时为 0.15，800mg/kg 时为 0.29）中观察到非线性分配，随着转运体介导的外排饱和，K 值随剂量增加而增加。相比之下，肺分配呈剂量依赖性降低（400mg/kg 时为 0.43，800mg/kg 时为 0.25），提示主动摄取饱和。L-乳酸给药降低了肝脏、纹状体和海马中的 K 值，增加了肺和脾中的 K 值。GHB 表现出组织特异性的非线性分布，这与单羧酸转运体的参与一致。这些观察到的复杂性可能是由于 MCT1 和 4 对 GHB 转运具有不同的亲和力和方向性。
