Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights.
Gender-based differences in brain and plasma pharmacokinetics of letrozole in sprague-dawley rats: Application of physiologically-based pharmacokinetic modeling to gain quantitative insights.
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DOI：
10.1371/journal.pone.0248579
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Desai PB
中科院分区：
文献类型：
--
作者：
Arora P;Gudelsky G;Desai PB
基于雌激素合成酶芳香化酶（CYP19A1）在高级别胶质瘤中大量表达的发现，芳香化酶抑制剂来曲唑正在临床前模型中作为一种新的药物治疗这种恶性肿瘤。在这里，我们研究了来曲唑在雄性和雌性Sprague-Dawley大鼠中单次和稳态给药后的全身和脑药代动力学。此外，我们采用基于生理的药代动力学（PBPK）模型来定量了解该药物的血脑屏障穿透性。来曲唑（4mg /kg）每日腹腔注射，连续5天（男性）和11天（女性），并在静脉血取样的同时进行脑内微透析采集脑细胞外液（ECF）。采用高效液相色谱法测定药物水平，采用WinNonlin®进行非区室分析。采用Simcyp动物模拟器结合指定的多室脑模型进行自下而上的PBPK方法。总的来说，在来曲唑的全身和脑药代动力学中观察到明显的性别差异。来曲唑在雌性大鼠体内的清除率要慢得多，导致血浆和脑内药物浓度明显升高。稳态下，雌性和雄性大鼠血浆AUC 0 ~ 24分别为103.0和24.8 μg*h/ml，脑ECF AUC 0 ~ 12分别为24.0和4.8 μg*h/ml。PBPK模型模拟的脑浓度曲线与观察到的曲线非常吻合。虽然在临床环境中没有观察到来曲唑PK的性别差异，但这些发现将指导该化合物临床前研究中的剂量优化。PBPK模型将作为一个重要的临床转化工具。
Based on the discovery that the estrogen synthase aromatase (CYP19A1) is abundantly expressed in high- grade gliomas, the aromatase inhibitor, letrozole is being investigated in pre-clinical models as a novel agent against this malignancy. Here, we investigated the systemic and brain pharmacokinetics of letrozole following single and steady state dosing in both male and female Sprague-Dawley rats. Furthermore, we employed physiologically-based pharmacokinetic (PBPK) modeling to gain quantitative insights into the blood-brain barrier penetration of this drug. Letrozole (4 mg/kg) was administered intraperitoneally daily for 5 days (for males) and 11 days (for females) and intracerebral microdialysis was performed for brain extracellular fluid (ECF) collection simultaneously with venous blood sampling. Drug levels were measured using HPLC and non-compartmental analysis was conducted employing WinNonlin®. Simcyp animal simulator was used for conducting bottom-up PBPK approach incorporating the specified multi-compartment brain model. Overall, marked gender-specific differences in the systemic and brain pharmacokinetics of letrozole were observed. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain drug concentrations. At steady state, the plasma AUC 0–24 was 103.0 and 24.8 μg*h/ml and brain ECF AUC 0–12 was 24.0 and 4.8 μg*h/ml in female and male rats, respectively. The PBPK model simulated brain concentration profiles were in close agreement with the observed profiles. While gender-specific differences in letrozole PK are not observed in the clinical setting, these findings will guide the dose optimization during pre-clinical investigations of this compound. The PBPK model will serve as an important clinical translational tool.
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