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- W2985129586 endingPage "105122" @default.
- W2985129586 startingPage "105122" @default.
- W2985129586 abstract "Seletalisib is an orally bioavailable selective inhibitor of phosphoinositide 3-kinase delta (PI3Kδ) in clinical development for the treatment of immune-mediated inflammatory diseases. The present study investigated the role of P-gp in seletalisib disposition, especially brain distribution, and the associated risks of interactions. Seletalisib was found to be actively transported by rodent and human P-gp in vitro (transfected LLC-PK1 cells; Km of ca. 20 µM), with minimal or no affinity for the other tested transporters. A distribution study in knockout rats (single oral dosing at 750 mg kg−1) showed that P-gp restricts the brain disposition of seletalisib while having minimal effect on its intestinal absorption. Restricted brain penetration was also observed in cynomolgus monkeys (single oral dosing at 30 mg kg−1) using brain microdialysis and cerebrospinal fluid sampling (Kp,uu of 0.09 and 0.24, respectively). These findings opened the question of potential pharmacokinetic interaction between seletalisib and P-gp inhibitors. In vitro, CsA inhibited the active transport of seletalisib with an IC50 of 0.13 µM. In rats, co-administration of high doses of CsA (bolus iv followed by continuous infusion) increased the brain distribution of seletalisib (single oral dosing at 5 mg kg−1). The observed data were found aligned with those predicted by in vitro-in vivo extrapolation. Based on the same extrapolation method combined with literature data, only very few P-gp inhibitors (i.e. CsA, quinine, quinidine) were predicted to increase the brain disposition of seletalisib in the clinical setting (maximal 3-fold changes)." @default.
- W2985129586 created "2019-11-22" @default.
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- W2985129586 date "2020-01-01" @default.
- W2985129586 modified "2023-09-27" @default.
- W2985129586 title "Role of P-glycoprotein in the brain disposition of seletalisib: Evaluation of the potential for drug-drug interactions" @default.
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- W2985129586 cites W1878847326 @default.
- W2985129586 cites W1968468357 @default.
- W2985129586 cites W1989359051 @default.
- W2985129586 cites W1994741969 @default.
- W2985129586 cites W1995603244 @default.
- W2985129586 cites W2005408062 @default.
- W2985129586 cites W2009169076 @default.
- W2985129586 cites W2017543810 @default.
- W2985129586 cites W2020103507 @default.
- W2985129586 cites W2027313042 @default.
- W2985129586 cites W2033243875 @default.
- W2985129586 cites W2038692868 @default.
- W2985129586 cites W2044392411 @default.
- W2985129586 cites W2049517140 @default.
- W2985129586 cites W2051018226 @default.
- W2985129586 cites W2058780134 @default.
- W2985129586 cites W2064808628 @default.
- W2985129586 cites W2077185661 @default.
- W2985129586 cites W2077495765 @default.
- W2985129586 cites W2078758206 @default.
- W2985129586 cites W2081866442 @default.
- W2985129586 cites W2094073838 @default.
- W2985129586 cites W2104930292 @default.
- W2985129586 cites W2107085652 @default.
- W2985129586 cites W2108982217 @default.
- W2985129586 cites W2110057699 @default.
- W2985129586 cites W2111917930 @default.
- W2985129586 cites W2124816030 @default.
- W2985129586 cites W2126513977 @default.
- W2985129586 cites W2131930718 @default.
- W2985129586 cites W2133475198 @default.
- W2985129586 cites W2133820236 @default.
- W2985129586 cites W2134086028 @default.
- W2985129586 cites W2134575967 @default.
- W2985129586 cites W2141017219 @default.
- W2985129586 cites W2155974380 @default.
- W2985129586 cites W2162611158 @default.
- W2985129586 cites W2166637794 @default.
- W2985129586 cites W2169526301 @default.
- W2985129586 cites W2171811002 @default.
- W2985129586 cites W2172147566 @default.
- W2985129586 cites W2257532993 @default.
- W2985129586 cites W2284156619 @default.
- W2985129586 cites W2287443485 @default.
- W2985129586 cites W2294766636 @default.
- W2985129586 cites W2316663096 @default.
- W2985129586 cites W2340000420 @default.
- W2985129586 cites W2417219779 @default.
- W2985129586 cites W2484611738 @default.
- W2985129586 cites W2519363128 @default.
- W2985129586 cites W2571511441 @default.
- W2985129586 cites W2576193666 @default.
- W2985129586 cites W2586013921 @default.
- W2985129586 cites W2590953783 @default.
- W2985129586 cites W2606880206 @default.
- W2985129586 cites W2607042209 @default.
- W2985129586 cites W2609809509 @default.
- W2985129586 cites W2661389864 @default.
- W2985129586 cites W2666802813 @default.
- W2985129586 cites W2735183447 @default.
- W2985129586 cites W2794069094 @default.
- W2985129586 cites W2809392875 @default.
- W2985129586 cites W2888672717 @default.
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- W2985129586 doi "https://doi.org/10.1016/j.ejps.2019.105122" @default.
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- W2985129586 hasPublicationYear "2020" @default.
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