Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2484681 | Journal of Pharmaceutical Sciences | 2014 | 10 Pages |
Abstract
Many weakly basic amineâcontaining drugs are known to be extensively sequestered in acidic lysosomes by an ion trappingâtype mechanism. The entrapment of drugs in lysosomes has been shown to influence drug activity, cancer cell selectivity, and pharmacokinetics and can cause the hyperaccumulation of various lipids associated with lysosomes. In this work, we have investigated the prolonged timeâdependent effects of drugs on lysosomal properties. We have evaluated two amineâcontaining drugs with intermediate (propranolol) and high (halofantrine) relative degrees of lipophilicity. Interestingly, the cellular accumulation kinetics of these drugs exhibited a biphasic characteristic at therapeutically relevant exposure levels with an initial apparent steadyâstate occurring at 2 days followed by a second stage of enhanced accumulation. We provide evidence that this secondary drug accumulation coincides with the nuclear localization of transcription factor EB, a master regulator of lysosome biogenesis, and the appearance of an increased number of smaller and lipidâladen lysosomes. Collectively, these results show that hydrophobic lysosomotropic drugs can induce their own cellular accumulation in a timeâdependent fashion and that this is associated with an expanded lysosomal volume. These results have important therapeutic implications and may help to explain sources of variability in drug pharmacokinetic distribution and elimination properties observed in vivo. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3287-3296, 2014
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Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Randall Logan, Alex C. Kong, Jeffrey P. Krise,