Use of In Vivo Imaging and Physiologically-Based Kinetic Modelling to Predict Hepatic Transporter Mediated Drug-Drug Interactions in Rats

• Những tác giả chính: Nicola Melillo (Tác giả), Daniel Scotcher (Tác giả), J. Gerry Kenna (Tác giả), Claudia Green (Tác giả), Catherine D. G. Hines (Tác giả), Iina Laitinen (Tác giả), Paul D. Hockings (Tác giả), Kayode Ogungbenro (Tác giả), Ebony R. Gunwhy (Tác giả), Steven Sourbron (Tác giả), John C. Waterton (Tác giả), Gunnar Schuetz (Tác giả), Aleksandra Galetin (Tác giả)
• Định dạng: Sách
• Được phát hành: MDPI AG, 2023-03-01T00:00:00Z.
• Những chủ đề: article
• Truy cập trực tuyến: Connect to this object online.

Tóm tắt

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 (k_he), and biliary excretion (k_bh). 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 k_he and k_bh 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 k_he (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.

Mô tả sách

10.3390/pharmaceutics15030896
1999-4923