Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug-Drug Interactions in Rats.
Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug-Drug Interactions in Rats.
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DOI：
10.3390/pharmaceutics15030896
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发表时间：
2023-03-10
期刊：
影响因子：
5.4
通讯作者：
Galetin A
中科院分区：
文献类型：
--
作者：
Melillo N;Scotcher D;Kenna JG;Green C;Hines CDG;Laitinen I;Hockings PD;Ogungbenro K;Gunwhy ER;Sourbron S;Waterton JC;Schuetz G;Galetin A
Gadoxetate是一种磁共振成像(MRI)造影剂，是有机阴离子转运多肽1b1和多药耐药相关蛋白2的底物。6种不同程度转运体抑制的药物被用于评估Gadoxetate动态增强MRI转运体抑制生物标志物。通过基于生理的药代动力学(PBPK)模型对转运蛋白调节导致的加多西特全身和肝脏AUC(AUCR)的变化进行前瞻性预测。用示踪动力学模型估算肝脏摄取(KHE)和胆汁排泄(KBH)的速率常数。观察到的加多西汀肝脏AUC的中位数分别是环孢素和利福平的3.8倍和1.5倍。酮康唑出人意料地降低了全身和肝脏的非洛西汀AUC；其余被研究的药物(阿索奈韦、波生坦和吡格列酮)引起了轻微的变化。环孢素使格多西汀的Khe和Kbh分别下降3.78和0.09毫升/分/毫升，而利福平分别下降7.20和0.07毫升/分/毫升。KHE的相对下降(例如，环孢素的96%)与PBPK预测的摄取抑制(97-98%)相似。PBPK模型正确地预测了加多西汀全身AUCR的变化，而对肝脏AUC减少的预测不足是显而易见的。目前的研究说明了肝脏成像数据、PBPK和示踪剂动力学模型的建模框架和集成，以期对人类肝脏转运体介导的DDI进行前瞻性量化。
Gadoxetate, a magnetic resonance imaging (MRI) contrast agent, is a substrate of organic-anion-transporting polypeptide 1B1 and multidrug resistance-associated protein 2. Six drugs, with varying degrees of transporter inhibition, were used to assess gadoxetate dynamic contrast enhanced MRI biomarkers for transporter inhibition in rats. Prospective prediction of changes in gadoxetate systemic and liver AUC (AUCR), resulting from transporter modulation, were performed by physiologically-based pharmacokinetic (PBPK) modelling. A tracer-kinetic model was used to estimate rate constants for hepatic uptake (khe), and biliary excretion (kbh). The observed median fold-decreases in gadoxetate liver AUC were 3.8- and 1.5-fold for ciclosporin and rifampicin, respectively. Ketoconazole unexpectedly decreased systemic and liver gadoxetate AUCs; the remaining drugs investigated (asunaprevir, bosentan, and pioglitazone) caused marginal changes. Ciclosporin decreased gadoxetate khe and kbh by 3.78 and 0.09 mL/min/mL, while decreases for rifampicin were 7.20 and 0.07 mL/min/mL, respectively. The relative decrease in khe (e.g., 96% for ciclosporin) was similar to PBPK-predicted inhibition of uptake (97–98%). PBPK modelling correctly predicted changes in gadoxetate systemic AUCR, whereas underprediction of decreases in liver AUCs was evident. The current study illustrates the modelling framework and integration of liver imaging data, PBPK, and tracer-kinetic models for prospective quantification of hepatic transporter-mediated DDI in humans.
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影响因子：
6.7
作者：
Georgiou L;Penny J;Nicholls G;Woodhouse N;Blé FX;Hubbard Cristinacce PL;Naish JH
通讯作者：
Naish JH
影响因子：
3.7
作者：
Karageorgis A;Lenhard SC;Yerby B;Forsgren MF;Liachenko S;Johansson E;Pilling MA;Peterson RA;Yang X;Williams DP;Ungersma SE;Morgan RE;Brouwer KLR;Jucker BM;Hockings PD
通讯作者：
Hockings PD
影响因子：
3.7
作者：
Gertz, Michael;Tsamandouras, Nikolaos;Galetin, Aleksandra
通讯作者：
Galetin, Aleksandra
影响因子：
6.7
作者：
Barnett, Shelby;Ogungbenro, Kayode;Galetin, Aleksandra
通讯作者：
Galetin, Aleksandra
影响因子：
3.7
作者：
Forsgren, Mikael Fredrik;Leinhard, Olof Dahlqvist;Lundberg, Peter
通讯作者：
Lundberg, Peter