The widespread use and high abuse liability of tobacco products has received considerable public health attention, in particular for youth, who are vulnerable to nicotine addiction. In this study, adult and adolescent squirrel monkeys were used to evaluate age-related metabolism and pharmacokinetics of nicotine after intravenous administration. A physiologically-based pharmacokinetic (PBPK) model was created to characterize the pharmacokinetic behaviors of nicotine and its metabolites, cotinine, trans-3'-hydroxycotinine (3'-OH cotinine), and trans-3'-hydroxycotinine glucuronide (3'-OH cotinine glucuronide) for both adult and adolescent squirrel monkeys. The PBPK nicotine model was first calibrated for adult squirrel monkeys utilizing in vitro nicotine metabolic data, plasma concentration-time profiles and cumulative urinary excretion data for nicotine and metabolites. Further model refinement was conducted when the calibrated adult model was scaled to the adolescents, because adolescents appeared to clear nicotine and cotinine more rapidly relative to adults. More specifically, the resultant model parameters representing systemic clearance of nicotine and cotinine for adolescent monkeys were approximately two- to three-fold of the adult values on a per body weight basis. The nonhuman primate PBPK model in general captured experimental observations that were used for both model calibration and evaluation, with acceptable performance metrics for precision and bias. The model also identified differences in nicotine pharmacokinetics between adolescent and adult nonhuman primates which might also be present in humans.

中文翻译：

---

使用基于生理学的药代动力学模型探讨成人和青少年非人类灵长类动物在尼古丁处置中的潜在差异。

烟草制品的广泛使用和高度滥用的责任已引起公众的广泛关注，特别是对于易受尼古丁成瘾影响的年轻人。在这项研究中，成年和青春期的松鼠猴被用来评估静脉给药后与年龄有关的新陈代谢和尼古丁的药代动力学。建立了基于生理的药代动力学（PBPK）模型来表征尼古丁及其代谢产物，可替宁，反式3'-羟基烟碱（3'-OH可替宁）和反式3'-羟基烟碱葡糖醛酸（3'- OH可替宁葡糖醛酸），适用于成年和青春期的松鼠猴。首先使用体外尼古丁代谢数据为成年松鼠猴校准PBPK尼古丁模型，血浆浓度-时间曲线以及尼古丁和代谢产物的累积尿排泄数据。当将校准后的成人模型缩放到青少年时，可以进行进一步的模型改进，因为相对于成人，青少年似乎更快地清除了尼古丁和可替宁。更具体地说，代表每只青春期猴子对尼古丁和可替宁的全身清除率的模型结果参数约为成人值的2到3倍。通常，非人类灵长类PBPK模型捕获了用于模型校准和评估的实验观察结果，并具有可接受的精度和偏差性能指标。