Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma.
Brain pharmacokinetics and metabolism of the AMP-activated protein kinase selective inhibitor SBI-0206965, an investigational agent for the treatment of glioblastoma.
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DOI：
10.1007/s10637-022-01278-8
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发表时间：
2022-10
影响因子：
3.4
通讯作者：
Desai, Pankaj B.
中科院分区：
文献类型：
--
作者：
Desai, Janki M.;Karve, Aniruddha S.;Gudelsky, Gary A.;Gawali, Mruniya, V;Seibel, William;Sallans, Larry;DasGupta, Biplab;Desai, Pankaj B.
关键词：
新出现的证据表明，5'腺苷单磷酸活化蛋白激酶（AMPK），细胞生物能量学的关键调节因子，是治疗胶质母细胞瘤（GBM），一种致命的脑肿瘤的新靶点。SBI-0206965是一种氨基嘧啶衍生物，是一种有效的AMPK抑制剂，正在研究用于治疗GBM。在此，我们描述了SBI-0206965的全身和脑药代动力学（PK）和肝脏代谢。我们进行了脑内微透析，以确定SBI-0206965在颈静脉插管大鼠中的脑分配。我们评估了大鼠和C57 BL/6小鼠经口给药后SBI-0206965的全身PK。采用人、小鼠和大鼠肝微粒体，我们表征了SBI-0206965的代谢。SBI-0206965吸收迅速，在0.25 - 0.65 h内达到血浆和脑细胞外液（ECF）峰值水平。基于脑ECF与血浆（针对蛋白结合校正）的Cmax和AUC比值，大鼠的脑分配约为0.6-0.9。然而，该化合物的消除半衰期较短（1-2 h），相对口服生物利用度较低（约0.15）。SBI-0206965在小鼠、大鼠和人中的估计体外肝脏固有清除率分别为325、76和68 mL/min/kg。SBI-0206965代谢产物包括去甲基化产物，代谢受到酮康唑（一种CYP 3A抑制剂）的强烈抑制。SBI-0206965具有足够的脑渗透性，但相对口服生物利用度较低，这可能是由于快速的肝脏代谢（可能由CYP 3A酶催化）造成的。我们的观察将促进SBI-0206965和/或其他结构相关分子的进一步开发，用于治疗GBM和其他脑肿瘤。
Emerging evidence suggests that 5’ Adenosine Monophosphate-Activated Protein Kinase (AMPK), a key regulator of cellular bioenergetics, is a novel target for the treatment of glioblastoma (GBM), a lethal brain tumor. SBI-0206965, an aminopyrimidine derivative, is a potent AMPK inhibitor being investigated for the treatment of GBM. Here we characterized the systemic and brain pharmacokinetics (PK) and hepatic metabolism of SBI-0206965. We performed intracerebral microdialysis to determine brain partitioning of SBI-0206965 in jugular vein cannulated rats. We assessed systemic PK of SBI-0206965 in rats and C57BL/6 mice following oral administration. Employing human, mouse, and rat liver microsomes we characterized the metabolism of SBI-0206965. SBI-0206965 is quickly absorbed, achieving plasma and brain extracellular fluid (ECF) peak levels within 0.25 – 0.65 h. Based on the ratio of Cmax and AUC in brain ECF to plasma (corrected for protein binding), brain partitioning is ~ 0.6—0.9 in rats. However, the compound has a short elimination half-life (1–2 h) and low relative oral bioavailability (~ 0.15). The estimated in-vitro hepatic intrinsic clearance of SBI-0206965 in mouse, rat and human was 325, 76 and 68 mL/min/kg, respectively. SBI-0206965 metabolites included desmethylated products, and the metabolism was strongly inhibited by ketoconazole, a CYP3A inhibitor. SBI-0206965 has adequate brain permeability but low relative oral bioavailability which may be due to rapid hepatic metabolism, likely catalyzed by CYP3A enzymes. Our observations will facilitate further development of SBI-0206965, and/or other structurally related molecules, for the treatment of GBM and other brain tumors.
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影响因子：
3.4
作者：
Lau, CE;Ma, F;Smith, C
通讯作者：
Smith, C
影响因子：
2
作者：
Adhikari, Bandita;Li, Jie;Carter, Bob S.
通讯作者：
Carter, Bob S.
影响因子：
3
作者：
Dave, Nimita;Gudelsky, Gary A.;Desai, Pankaj B.
通讯作者：
Desai, Pankaj B.
研究ULK1/AMPK抑制剂SBI-0206965的特异性和作用机理。
DOI：
10.1042/bcj20210284
发表时间：
2021-08-13
期刊：
The Biochemical journal
影响因子：
--
作者：
Ahwazi D;Neopane K;Markby GR;Kopietz F;Ovens AJ;Dall M;Hassing AS;Gräsle P;Alshuweishi Y;Treebak JT;Salt IP;Göransson O;Zeqiraj E;Scott JW;Sakamoto K
通讯作者：
Sakamoto K
影响因子：
3.7
作者：
Arora P;Gudelsky G;Desai PB
通讯作者：
Desai PB