Lysosomal sequestration of amine-containing drugs: analysis and therapeutic implications.
Amine-containing drugs represent a very important class of therapeutic agents, with the majority of all drugs containing at least one basic nitrogen. For many decades, it has been known that weakly basic compounds can be sequestered into acidic organelles such as lysosomes. Some amines can achieve very high concentrations and induce a dramatic expansion (vacuolization) of the compartment. In the early 70s, Nobel laureate and discoverer of lysosomes, Christian de Duve et al. wrote an elegant commentary describing the theoretical basis for lysosomal sequestration of amines, referring to the process as pH-partitioning and the substrates as lysosomotropics. Recently, a resurgence of interest in the intracellular distribution of drugs has occurred considering its therapeutic importance. Specifically, lysosomal sequestration of amines has received considerable attention for reasons including its involvement in drug resistance, inducement of phospholipidosis, and its influence on whole body distribution/pharmacokinetics. Moreover, the sequestration phenomenon has been recently exploited in the development of a novel drug targeting strategy. This review will focus on these occurrences/developments and conclude with a commentary on the expected impact that knowledge regarding the intracellular distribution of drugs will likely have on future drug development processes.
Kaufmann
Allyn M
AM
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
Krise
Jeffrey P
JP
D000588:Amines / Q000378:metabolism*; D016503:Drug Delivery Systems; D015195:Drug Design; D008247:Lysosomes / Q000378:metabolism*
D000588:Amines