Quantitative Analysis of the Phase Transition Mechanism Underpinning the Systemic Self-Assembly of a Mechanopharmaceutical Device.
Quantitative Analysis of the Phase Transition Mechanism Underpinning the Systemic Self-Assembly of a Mechanopharmaceutical Device.
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DOI：
10.3390/pharmaceutics14010015
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发表时间：
2021-12-22
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：
Dunne S;Willmer AR;Swanson R;Almeida D;Ammerman NC;Stringer KA;Capparelli EV;Rosania GR
氯法齐明（CFZ）是一种难溶、弱碱性的小分子抗生素，临床上用于治疗麻风病，目前正在进行临床试验，用于治疗多药耐药结核病和COVID-19。CFZ具有复杂的背景依赖性药代动力学，其特征在于在长期治疗方案中半衰期增加。CFZ的全身药代动力学先前已由非线性二室模型表示，该模型包含扩展的分布容积。这种膨胀反映了药物在其沉淀出来并积聚在遍布生物体的巨噬细胞内时所经历的可溶性到不溶性的相变。使用小鼠作为模型生物，我们研究了这种增加半衰期的机制基础以及CFZ的全身药代动力学如何随着持续给药而改变。为此，M。结核感染状况和多次给药方案的研究，以及参数敏感性分析（PSA），以进一步了解全身药物分布。控制捕获相变的S形展开函数的参数值被系统地改变，并且依次计算药物的全身浓度，并与血清和脾脏中实验测量的药物浓度进行比较。所得到的药物隔离量取决于给予的CFZ的总质量和药物负载的持续时间。这种现象可以通过改变对应于负责巨噬细胞中不溶性药物物质沉淀和积累的关键生物决定因素的扩展函数的三个不同参数来捕获。通过这种上下文相关的CFZ的药代动力学的分析，可以构建预测框架，用于预测沉淀的药物复合物的全身分布和自组装，作为这种和其他药物表现出类似复杂的药代动力学的细胞内机械药物装置。
Clofazimine (CFZ) is a poorly soluble, weakly basic, small molecule antibiotic clinically used to treat leprosy and is now in clinical trials as a treatment for multidrug resistant tuberculosis and COVID-19. CFZ exhibits complex, context-dependent pharmacokinetics that are characterized by an increasing half-life in long term treatment regimens. The systemic pharmacokinetics of CFZ have been previously represented by a nonlinear, 2-compartment model incorporating an expanding volume of distribution. This expansion reflects the soluble-to-insoluble phase transition that the drug undergoes as it precipitates out and accumulates within macrophages disseminated throughout the organism. Using mice as a model organism, we studied the mechanistic underpinnings of this increasing half-life and how the systemic pharmacokinetics of CFZ are altered with continued dosing. To this end, M. tuberculosis infection status and multiple dosing schemes were studied alongside a parameter sensitivity analysis (PSA) to further understanding of systemic drug distribution. Parameter values governing the sigmoidal expansion function that captures the phase transition were methodically varied, and in turn, the systemic concentrations of the drug were calculated and compared to the experimentally measured concentrations of drug in serum and spleen. The resulting amounts of drug sequestered were dependent on the total mass of CFZ administered and the duration of drug loading. This phenomenon can be captured by altering three different parameters of an expansion function corresponding to key biological determinants responsible for the precipitation and the accumulation of the insoluble drug mass in macrophages. Through this analysis of the context dependent pharmacokinetics of CFZ, a predictive framework for projecting the systemic distribution and self-assembly of precipitated drug complexes as intracellular mechanopharmaceutical devices of this and other drugs exhibiting similarly complex pharmacokinetics can be constructed.
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影响因子：
4.6
作者：
Woldemichael T;Keswani RK;Rzeczycki PM;Murashov MD;LaLone V;Gregorka B;Swanson JA;Stringer KA;Rosania GR
通讯作者：
Rosania GR
影响因子：
64.8
作者：
Riva L;Yuan S;Yin X;Martin-Sancho L;Matsunaga N;Pache L;Burgstaller-Muehlbacher S;De Jesus PD;Teriete P;Hull MV;Chang MW;Chan JF;Cao J;Poon VK;Herbert KM;Cheng K;Nguyen TH;Rubanov A;Pu Y;Nguyen C;Choi A;Rathnasinghe R;Schotsaert M;Miorin L;Dejosez M;Zwaka TP;Sit KY;Martinez-Sobrido L;Liu WC;White KM;Chapman ME;Lendy EK;Glynne RJ;Albrecht R;Ruppin E;Mesecar AD;Johnson JR;Benner C;Sun R;Schultz PG;Su AI;García-Sastre A;Chatterjee AK;Yuen KY;Chanda SK
通讯作者：
Chanda SK
影响因子：
4.9
作者：
Baik, Jason;Stringer, Kathleen A.;Rosania, Gus R.
通讯作者：
Rosania, Gus R.
影响因子：
3.4
作者：
Miller, WH;Hartmann-Siantar, C;Volkert, WA
通讯作者：
Volkert, WA
DOI：
10.1093/jac/dkaa310
发表时间：
2020-11-01
期刊：
The Journal of antimicrobial chemotherapy
影响因子：
--
作者：
Abdelwahab MT;Wasserman S;Brust JCM;Gandhi NR;Meintjes G;Everitt D;Diacon A;Dawson R;Wiesner L;Svensson EM;Maartens G;Denti P
通讯作者：
Denti P