RT Journal Article
SR Electronic
T1 Lysosomal Biogenesis and Implications for Hydroxychloroquine Disposition
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2020-000309
DO 10.1124/jpet.120.000309
A1 Keagan P Collins
A1 Sandra Witta
A1 Jonathan Coy
A1 Yi Pang
A1 Daniel L. Gustafson
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/11/10/jpet.120.000309.abstract
AB Lysosomes act as a cellular drug sink for weakly basic, lipophilic (lysosomotropic) xenobiotics, with many instances of lysosomal trapping associated with MDR. Lysosomotropic agents have also been shown to activate master lysosomal biogenesis transcription factor EB (TFEB), and ultimately lysosomal biogenesis. We investigated the role of lysosomal biogenesis in the disposition of hydroxychloroquine (HCQ), a hallmark lysosomotropic agent, and observed that modulating the lysosomal volume of human breast cancer cell lines can account for differences in disposition of HCQ. Through use of an in vitro pharmacokinetic (PK) model we characterized total cellular uptake of HCQ within the duration of static equilibrium (1 hour), as well as extended exposure to HCQ that are subject to dynamic equilibrium (>1 hour) wherein HCQ increases the size of the lysosomal compartment through swelling and TFEB-induced lysosomal biogenesis. In addition, we show that pretreatment of cell lines with TFEB-activating agent Torin 1 contributed to an increase of HCQ whole cell concentrations by 1.4 to 1.6-fold, which were also characterized by the in vitro PK model. This investigation into the role of lysosomal volume dynamics in lysosomotropic drug disposition, including the ability of HCQ to modify its own disposition, advances our understanding of how chemically-similar agents may distribute on the cellular level, and examines a key area of lysosomal-mediated MDR and DDI. Significance Statement Hydroxychloroquine is able to modulate its own cellular pharmacokinetic uptake by increasing the cellular lysosomal volume fraction through activation of lysosomal biogenesis master transcription factor EB, and through lysosomal swelling. This concept can be applied to many other lysosomotropic drugs that activate TFEB, such as doxorubicin and other TKI drugs, where these drugs may actively increase their own sequestration within the lysosome to further exacerbate MDR and lead to potential acquired resistance.