Yu X Q, Kramer J, Moran L, O'Neill E, Nouraldeen A, Oravecz T, Wilson A G E
Department of Drug Metabolism, Pharmacokinetics, Toxicology and Pathology, Lexicon Pharmaceuticals, Inc., The Woodlands, TX 77381, USA.
Xenobiotica. 2010 May;40(5):350-6. doi: 10.3109/00498251003611376.
2-Acetyl-4(5)-tetrahydroxybutyl imidazole (THI) has been shown to reduce rodent peripheral blood lymphocytes through increasing lymphoid sphingosine 1-phosphate (S1P) by inhibiting S1P lyase. The objective of this study was to characterize the relationship between systemic THI exposure, splenic S1P concentrations, and lymphopenia in rats. Following the oral administration of 10 and 100 mg kg(-1) THI to male rats, THI was rapidly absorbed and reached a plasma peak level at 1 h post-dosing. Splenic S1P increased and reached the peak level at 24 h. Blood lymphocyte count decreased as the splenic S1P level increased. THI plasma concentration was linked to splenic S1P concentration using an indirect model incorporated with a four-step signal transduction model. In turn, the S1P level was directly coupled with blood lymphocyte number. The integrated model simultaneously captured the splenic S1P and blood lymphocyte responses. This pharmacokinetic-biomarker-pharmacodynamic model resolved the remarkable discrepancy between plasma THI concentration and the pharmacological response and quantitatively described the relationship of THI exposure, S1P, and lymphopenic response.
2-乙酰基-4(5)-四羟基丁基咪唑（THI）已被证明可通过抑制鞘氨醇-1-磷酸（S1P）裂解酶来增加淋巴鞘氨醇-1-磷酸，从而减少啮齿动物外周血淋巴细胞。本研究的目的是表征大鼠全身THI暴露、脾脏S1P浓度和淋巴细胞减少之间的关系。给雄性大鼠口服10和100 mg kg(-1) THI后，THI迅速吸收，并在给药后1小时达到血浆峰值水平。脾脏S1P增加，并在24小时达到峰值水平。随着脾脏S1P水平的增加，血液淋巴细胞计数减少。使用结合四步信号转导模型的间接模型将THI血浆浓度与脾脏S1P浓度联系起来。反过来，S1P水平与血液淋巴细胞数量直接相关。综合模型同时捕捉到了脾脏S1P和血液淋巴细胞反应。这种药代动力学-生物标志物-药效学模型解决了血浆THI浓度与药理反应之间的显著差异，并定量描述了THI暴露、S1P和淋巴细胞减少反应之间的关系。
