title: Evaluating the roles of autophagy and lysosomal trafficking defects in intracellular distribution-based drug-drug interactions involving lysosomes.
abstract: Many currently approved drugs possess weakly basic properties that make them substrates for extensive sequestration in acidic intracellular compartments such as lysosomes through an ion trapping-type mechanism. Lysosomotropic drugs often have unique pharmacokinetic properties that stem from the extensive entrapment in lysosomes, including an extremely large volume of distribution and a long half-life. Accordingly, pharmacokinetic drug-drug interactions can occur when one drug modifies lysosomal volume such that the degree of lysosomal sequestration of secondarily administered drugs is significantly altered. In this work, we have investigated potential mechanisms for drug-induced alterations in lysosomal volume that give rise to drug-drug interactions involving lysosomes. We show that eight hydrophobic amines, previously characterized as perpetrators in this type of drug-drug interaction, cause a significant expansion in lysosomal volume that was correlated with both the induction of autophagy and with decreases in the efficiency of lysosomal egress. We also show that well-known chemical inducers of autophagy caused an increase in apparent lysosomal volume and an increase in secondarily administered lysosomotropic drugs without negatively impacting vesicle-mediated lysosomal egress. These results could help rationalize how the induction of autophagy could cause variability in the pharmacokinetic properties of lysosomotropic drugs.
authors: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas, 66047.
authors: Randall
authors: R
authors: Logan
authors: Alex
authors: A
authors: Kong
authors: Jeffrey P
authors: JP
authors: Krise
mesh_terms: D000588:Amines / Q000737:chemistry / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D002460:Cell Line; D004347:Drug Interactions; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D009288:Naproxen / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000588:Amines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009288:Naproxen
keywords: cell biology; cell culture; doseresponse; drug interactions; in vitro models; pharamcokinetics; physicochemical properties