Lysosomal-mediated drug resistance – Fact or illusion?
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F24%3A73624591" target="_blank" >RIV/61989592:15110/24:73624591 - isvavai.cz</a>
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S104366182300381X?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S104366182300381X?via%3Dihub</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.phrs.2023.107025" target="_blank" >10.1016/j.phrs.2023.107025</a>
Alternative languages
Result language
angličtina
Original language name
Lysosomal-mediated drug resistance – Fact or illusion?
Original language description
pH gradients across cell membranes affect the intracellular distribution of hydrophobic weak-base anticancer agents. This significantly reduces their availability at target sites, reducing cytotoxic effect and leading to drug resistance. This hypothetical in vitro study evaluates the impact of two important pH gradients on the intracellular distribution of such drugs in tumor cells.Calculations with simplified models clearly show that even a relatively small pH gradient between cytosol and extracellular environment can dramatically reduce the intracellular concentration of weak-base drugs. This is only slightly affected by the pKa or number of cells. However, if the later is enormous and the volume ratio between extracellular environment and target site (cytosol) decreases significantly, the pH gradient has little effect on the drug concentration at target site. In contrast, even a large pH gradient between lysosomes and cytosol has only marginal impact on the intracellular drug distribution. The effects of the drug pKa or number of cells are also small here. Only extremely acidic lysosomal pH or enormous lysosome size have substantial impact on the target site concentration of weak-base drugs, although the significance of these effects is questionable.In conclusion, the volume ratio between the drug “trapping” and target sites is a crucial factor in the ability of pH gradients to change target site drug concentrations. Accordingly, the pH gradient between cytosol and extracellular environment has a much greater impact on the intracellular distribution of hydrophobic weak-base drugs than that between lysosomes and cytosol under standard conditions in laboratory experiments.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30104 - Pharmacology and pharmacy
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2024
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
PHARMACOLOGICAL RESEARCH
ISSN
1043-6618
e-ISSN
1096-1186
Volume of the periodical
199
Issue of the periodical within the volume
January 2024
Country of publishing house
GB - UNITED KINGDOM
Number of pages
3
Pages from-to
107025
UT code for WoS article
001143368600001
EID of the result in the Scopus database
2-s2.0-85180360444