Lysosomotropism
Weak bases with lipophilic properties accumulate in acidic intracellular compartments like lysosomes. While the plasma and lysosomal membranes are permeable for neutral and uncharged species of weak bases, the charged protonated species of weak bases do not permeate biomembranes and accumulate within lysosomes. The concentration within lysosomes may reach levels 100 to 1000 fold higher than extracellular concentrations. This phenomenon is called "lysosomotropism" or "acid trapping". The amount of accumulation of lysosomotropic compounds may be estimated using a cell based mathematical model.
A significant part of the clinically approved drugs are lipophilic weak bases with lysosomotropic properties. This explaines a number of pharmacological properties of these drugs, such as high tissue-to-blood concentration gradients or long tissue elimination half-lifes; these properties have been found for drugs such as haloperidol, levomepromazine and amantadine. However, in addition to high tissue concentrations and long elimination half-life is explained also by lipophilicity and absorption of drugs to fatty tissue structures. Important lysosomal enzymes, such as acid sphingomyelinase, may be inhibited by lysososomally accumulated drugs. Such compounds are termed FIASMAs (functional inhibitor of acid sphingomyelinase) and include for example fluoxetine, sertraline or amitriptyline.
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