Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications

Abstract

Introduction: Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered.

Areas covered: In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing.

Expert opinion: Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

Keywords::

• cationic amphipathic drug (CAD)
• drug sequestration
• drug-drug interaction
• hydrophobic amine
• ion trapping
• lipidosis
• lysosomal pH
• lysosomal volume
• lysosomes
• Niemann pick disease (NPC)
• pH partitioning

Declaration of interest

R Logan and R Funk are supported by a Biotech Training Grant (T32-GM008359) and R Logan is also supported by means of a pharmaceutics pre-doctoral fellowship from the PhRMA Foundation. E Axcell and J Krise declare that they have no conflict of interest to declare and have received no payment in the preparation of this manuscript.

Notes

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