Sex and Cross-Sex Testosterone Treatment Alters Gamma-Hydroxybutyrate Acid Toxicokinetics and Toxicodynamics in Rats.
Sex and Cross-Sex Testosterone Treatment Alters Gamma-Hydroxybutyrate Acid Toxicokinetics and Toxicodynamics in Rats.
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DOI：
10.3390/pharmaceutics16010143
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发表时间：
2024-01-21
期刊：
影响因子：
5.4
通讯作者：
Felmlee MA
中科院分区：
文献类型：
--
作者：
Zhang Q;Wei H;Lee A;Felmlee MA
γ-羟基丁酸（GHB）因其镇静/催眠和欣快作用而被广泛滥用。近年来，LGBTQ+ 群体中 GHB 的使用显着增加。 GHB 是单羧酸转运蛋白 (MCT) 的底物，表现出非线性毒代动力学，其特点是可饱和代谢、吸收和肾脏重吸收。本研究调查了外源性睾酮给药对 GHB 毒代动力学和毒效动力学的影响，探索 MCT1 抑制作为抵消毒性策略的潜力。切除卵巢 (OVX) 的雌性和去势 (CST) 的雄性 Sprague Dawley 大鼠接受睾酮或安慰剂治疗 21 天。 GHB以两种剂量（1000 mg/kg或1500 mg/kg i.v.）施用，并在GHB（1500 mg/kg i.v.）施用后5分钟施用MCT1抑制剂AR-C 155858（1 mg/kg i.v.）。给药后 8 小时内收集血浆和尿液，并通过经过验证的 LC/MS/MS 测定对 GHB 浓度进行定量。睡眠时间（镇静/催眠作用）被用作毒动力学终点。睾酮治疗显着影响 GHB 毒代动力学和毒效动力学。睾酮治疗的 CST 大鼠表现出显着较低的肾清除率、较高的 AUC 和增强的镇静作用，而睾酮治疗的 OVX 大鼠则表现出较高的代谢清除率。 AR-C 155858 治疗导致 GHB 肾清除率和总清除率增加，同时镇静/催眠效果有所改善。总之，外源性睾酮治疗会引起 GHB 毒代动力学和毒效动力学的显着改变，MCT 抑制可以作为顺性别和跨性别男性群体中 GHB 过量的潜在治疗策略。
Γ-hydroxybutyric acid (GHB) is widely abused due to its sedative/hypnotic and euphoric effects. In recent years, GHB use has witnessed a notable rise within the LGBTQ+ community. GHB is a substrate of monocarboxylate transporters (MCTs) and exhibits nonlinear toxicokinetics, characterized by saturable metabolism, absorption, and renal reabsorption. This study investigates the impact of exogenous testosterone administration on GHB toxicokinetics and toxicodynamics, exploring the potential of MCT1 inhibition as a strategy to counteract toxicity. Ovariectomized (OVX) females and castrated (CST) male Sprague Dawley rats were treated with testosterone or placebo for 21 days. GHB was administered at two doses (1000 mg/kg or 1500 mg/kg i.v.), and the MCT1 inhibitor AR-C 155858 (1 mg/kg i.v.) was administered 5 min after GHB (1500 mg/kg i.v.) administration. Plasma and urine were collected up to 8 h post-dose, and GHB concentrations were quantified via a validated LC/MS/MS assay. Sleep time (sedative/hypnotic effect) was utilized as the toxicodynamic endpoint. Testosterone treatment significantly affected GHB toxicokinetics and toxicodynamics. Testosterone-treated CST rats exhibited significantly lower renal clearance, higher AUC, and increased sedative effect, while testosterone-treated OVX rats demonstrated higher metabolic clearance. AR-C 155858 treatment led to an increase in GHB renal and total clearance together with an improvement in sedative/hypnotic effect. In conclusion, exogenous testosterone treatment induces significant alterations in GHB toxicokinetics and toxicodynamics, and MCT inhibition can serve as a potential therapeutic strategy for GHB overdose in both cisgender and transgender male populations.
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