Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse.
Pharmacokinetic analysis of acute and dietary exposure to piperonyl butoxide in the mouse.
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对小鼠中急性和饮食中急性丁酰胺的药代动力学分析。
DOI：
10.1016/j.toxrep.2023.09.017
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发表时间：
2023-12
影响因子：
--
通讯作者：
Lipinski, Robert J
中科院分区：
文献类型：
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作者：
Jenkins, Alyssa E;Scarlett, Cameron O;Beames, Tyler G;Rivera-Gonzalez, Kenneth S;Martin, Alexander A;Sun, Miranda R;Hutson, Paul R;Lipinski, Robert J
丁醚双壬酯（PBO）是一种流行的杀虫剂，存在于成千上万的商业，农业和家庭产品中。PBO抑制细胞色素P450活性，损害昆虫解毒杀虫剂的能力。最近发现PBO还能抑制Sonic hedgehog信号传导（胚胎发育所需的一种途径），啮齿动物研究表明，宫内PBO暴露有可能导致大脑、面部和四肢的结构畸形，或更微妙的神经发育异常。目前对PBO在小鼠中的药代动力学的理解是有限的，特别是在与发育毒性相关的给药模式方面。为了建立口服暴露的药代动力学（PK）模型，通过口服管饲法（22-1800 mg/kg）或通过饮食（食物中0.09%PBO）将PBO急性施用给雌性C57 BL/6 J小鼠。收集血清和脂肪样品，并通过HPLC-MS/MS测定PBO浓度。PBO的血清浓度通过线性一室模型最佳拟合。PBO在内脏脂肪组织中的浓度大大超过血清中的浓度。停止膳食暴露后，血清和脂肪组织中的PBO浓度迅速下降。灌胃给药后PBO在小鼠中的消除半衰期为6.5 h（90% CI 4.7-9.5 h），全身口服清除率为83.3 ± 20.5 mL/h。PBO在食物中的生物利用度是通过管饲法在橄榄油中递送的PBO的41%。该PK模型的建立为将啮齿动物模型中引起发育毒性的PBO浓度与Sonic hedgehog信号通路抑制相关提供了基础。胡椒基丁醚在小鼠体内药动学模型的建立。通过经口灌胃或饮食向小鼠施用农药胡椒基丁醚。在处理后的多个时间点收集血清和脂肪组织。定量测定丁醚酮含量，以建立急性和亚慢性饮食暴露后的药代动力学模型。建立了PBO暴露在小鼠体内的药代动力学模型。PBO浓度定量后，急性或饮食暴露的HPLC-MS/MS。脂肪中PBO浓度超过血清中观察到的浓度。组织PBO浓度迅速下降后停止接触。这些结果为PBO相关的不良发育结局提供了新的见解。
Piperonyl butoxide (PBO) is a popular insecticide synergist present in thousands of commercial, agricultural, and household products. PBO inhibits cytochrome P450 activity, impairing the ability of insects to detoxify insecticides. PBO was recently discovered to also inhibit Sonic hedgehog signaling, a pathway required for embryonic development, and rodent studies have demonstrated the potential for in utero PBO exposure to cause structural malformations of the brain, face, and limbs, or more subtle neurodevelopmental abnormalities. The current understanding of the pharmacokinetics of PBO in mice is limited, particularly with respect to dosing paradigms associated with developmental toxicity. To establish a pharmacokinetic (PK) model for oral exposure, PBO was administered to female C57BL/6J mice acutely by oral gavage (22–1800 mg/kg) or via diet (0.09 % PBO in chow). Serum and adipose samples were collected, and PBO concentrations were determined by HPLC-MS/MS. The serum concentrations of PBO were best fit by a linear one-compartment model. PBO concentrations in visceral adipose tissue greatly exceeded those in serum. PBO concentrations in both serum and adipose tissue decreased quickly after cessation of dietary exposure. The elimination half-life of PBO in the mouse after gavage dosing was 6.5 h (90 % CI 4.7–9.5 h), and systemic oral clearance was 83.3 ± 20.5 mL/h. The bioavailability of PBO in chow was 41 % that of PBO delivered in olive oil by gavage. Establishment of this PK model provides a foundation for relating PBO concentrations that cause developmental toxicity in the rodent models to Sonic hedgehog signaling pathway inhibition. Establishing a model of piperonyl butoxide pharmacokinetics in the mouse. The pesticide synergist piperonyl butoxide was administered to mice through oral gavage or diet. Blood serum and adipose tissue were collected at multiple timepoints following treatment. Piperonyl butoxide content was quantitated to develop a pharmacokinetic model following both acute and sub-chronic dietary exposures. A pharmacokinetic model for PBO exposure in the mouse was established. PBO concentrations were quantified by HPLC-MS/MS after acute or dietary exposure. PBO concentrations in adipose exceeded those observed in serum. Tissue PBO concentrations decreased rapidly following cessation of exposure. These results offer new insight into PBO-associated adverse developmental outcomes.