Distinguishing the Concentration- vs. Bioaccumulation-Dependent Immunological and Metabolic Effects of Clofazimine.
Distinguishing the Concentration- vs. Bioaccumulation-Dependent Immunological and Metabolic Effects of Clofazimine.
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DOI：
10.3390/pharmaceutics15092350
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发表时间：
2023-09-20
期刊：
影响因子：
5.4
通讯作者：
Rosania GR
中科院分区：
文献类型：
--
作者：
Willmer AR;Diaz-Espinosa J;Zhou A;Stringer KA;Rosania GR
抗分枝杆菌药物氯法齐明（CFZ）被用作高剂量的单一药物，以抑制与麻风病相关的过度炎症。巧合的是，在生理学相关给药方案下，增加CFZ剂量导致CFZ在脾脏和其他器官中的生物蓄积，而不伴随血液中循环药物浓度的剂量依赖性升高。在长期口服给药方案中，CFZ诱导免疫和代谢变化，导致脾肿大，而其他器官的质量减少或保持不变。作为一个器官，广泛隔离CFZ作为不溶性药物沉淀，脾脏可能会影响药物诱导的炎症信号。为了探索全身药物浓度与脾脏中药物生物蓄积的作用，健康小鼠用六种不同的给药方案处理。这些小鼠中的一个亚组在药物治疗前进行了脾切除术，以评估免疫系统信号传导和免疫系统介导的药物分布的生物蓄积依赖性变化。在增加的药物负荷下，观察到脾脏的大小增长到6倍，螯合超过10%的总药物负荷。有趣的是，当在CFZ给药前切除脾脏时，药物在生物体其余部分的分布不受影响。然而，在无脾CFZ处理的小鼠的血清中存在显著的细胞因子升高，表明脾主要参与抑制CFZ生物蓄积期间上调的炎症信号传导机制。因此，除了其在药物螯合中的作用外，脾脏还积极调节CFZ对免疫系统的全身作用，而不影响其血液浓度或分布到生物体的其余部分。
The antimycobacterial drug clofazimine (CFZ) is used as a single agent at high doses, to suppress the exaggerated inflammation associated with leprosy. Paradoxically, increasing doses of CFZ leads to bioaccumulation of CFZ in the spleen and other organs under physiologically relevant dosing regimens, without accompanying dose-dependent elevation in the concentrations of the circulating drug in the blood. In long-term oral dosing regimens, CFZ induces immunological and metabolic changes resulting in splenomegaly, while the mass of other organs decreases or remains unchanged. As an organ that extensively sequesters CFZ as insoluble drug precipitates, the spleen likely influences drug-induced inflammatory signaling. To probe the role of systemic drug concentrations vs. drug bioaccumulation in the spleen, healthy mice were treated with six different dosing regimens. A subgroup of these mice underwent surgical splenectomies prior to drug treatment to assess the bioaccumulation-dependent changes in immune system signaling and immune-system-mediated drug distribution. Under increasing drug loading, the spleen was observed to grow up to six times in size, sequestering over 10% of the total drug load. Interestingly, when the spleen was removed prior to CFZ administration, drug distribution in the rest of the organism was unaffected. However, there were profound cytokine elevations in the serum of asplenic CFZ-treated mice, indicating that the spleen is primarily involved in suppressing the inflammatory signaling mechanisms that are upregulated during CFZ bioaccumulation. Thus, beyond its role in drug sequestration, the spleen actively modulates the systemic effect of CFZ on the immune system, without impacting its blood concentrations or distribution to the rest of the organism.
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DOI：
10.1016/j.jid.2017.09.031
发表时间：
2018-03
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Murashov MD;LaLone V;Rzeczycki PM;Keswani RK;Yoon GS;Sud S;Rajeswaran W;Larsen S;Stringer KA;Rosania GR
通讯作者：
Rosania GR
影响因子：
3.8
作者：
Degang Y;Akama T;Hara T;Tanigawa K;Ishido Y;Gidoh M;Makino M;Ishii N;Suzuki K
通讯作者：
Suzuki K
影响因子：
5.4
作者：
Dunne S;Willmer AR;Swanson R;Almeida D;Ammerman NC;Stringer KA;Capparelli EV;Rosania GR
通讯作者：
Rosania GR
影响因子：
10.1
作者：
Kristinsson, Sigurdur Y.;Gridley, Gloria;Landgren, Ola
通讯作者：
Landgren, Ola
影响因子：
4.9
作者：
Baik, Jason;Stringer, Kathleen A.;Rosania, Gus R.
通讯作者：
Rosania, Gus R.