Curriculum in Toxicology, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina, USA.
Toxicol Sci. 2010 Jun;115(2):330-43. doi: 10.1093/toxsci/kfq051. Epub 2010 Mar 3.
Mirfazaelian et al. developed a physiologically based pharmacokinetic (PBPK) model for the pyrethroid pesticide deltamethrin in the rat. This model describes gastrointestinal (GI) tract absorption as a saturable process mediated by phase III efflux transporters which pump deltamethrin out of the intestinal enterocytes into the GI tract lumen, resulting in minimal net absorption at low concentrations and increasing absorption at higher concentrations. In the present study, the dose dependency in absorption of deltamethrin was examined in male Long Evans rats using po exposures predicted by the Mirfazaelian model to yield different po bioavailability values. No difference in the bioavailability from single po doses of 0.3 and 3.0 mg/kg deltamethrin was observed. Based on this finding, the Mirfazaelian PBPK model was modified to exclude a saturable absorption process. Other changes to the Mirfazaelian model included describing all tissue compartments with diffusion-limited kinetics and a single blood compartment. These changes improved model predictions of deltamethrin tissue concentration data from the present study and the literature. The rat model was then scaled to humans. The model predicted a twofold greater peak deltamethrin brain concentration and threefold greater area under the curve (AUC(0-48 h)) for humans following an po exposure of 1 mg/kg. Based on this model, humans would have greater distribution of deltamethrin to the brain for the same administered po dose compared to rats. The relative sensitivity to deltamethrin between rats and humans depends on both pharmacokinetic and pharmacodynamic differences. Species differences in the pharmacodynamic responses to deltamethrin between rats and humans remain uncharacterized.
米尔法扎利安等人开发了一种用于拟除虫菊酯杀虫剂溴氰菊酯的基于生理学的药代动力学（PBPK）模型，该模型描述了胃肠道（GI）吸收是一个由 III 相外排转运体介导的饱和过程，该转运体将溴氰菊酯从肠上皮细胞泵入 GI 腔，导致在低浓度下最小的净吸收，在高浓度下吸收增加。在本研究中，使用 Mirfazaelian 模型预测的 po 暴露，在雄性 Long Evans 大鼠中检查了溴氰菊酯吸收的剂量依赖性，以产生不同的 po 生物利用度值。单次给予 0.3 和 3.0 mg/kg 溴氰菊酯的 po 剂量，生物利用度无差异。基于这一发现，对 Mirfazaelian PBPK 模型进行了修改，排除了饱和吸收过程。对 Mirfazaelian 模型的其他修改包括用扩散限制动力学和单个血液隔室描述所有组织隔室。这些修改改进了模型对本研究和文献中溴氰菊酯组织浓度数据的预测。然后将大鼠模型扩展到人类。该模型预测，人类在 po 暴露 1mg/kg 后，大脑中溴氰菊酯的峰值浓度增加两倍，曲线下面积（0-48 小时）增加三倍。基于该模型，与大鼠相比，po 给予相同剂量时，人类大脑中溴氰菊酯的分布更大。大鼠和人类之间对溴氰菊酯的相对敏感性取决于药代动力学和药效学的差异。大鼠和人类之间对溴氰菊酯的药效学反应的种间差异仍未确定。
