Phospholipidosis

The combination of hydrophilic and hydrophobic parts of a molecule defines its amphiphilicity. A program has been described to calculate this property and calibrated against experimental values obtained from surface activity measurements [133]. These values can possibly be used to predict effect on membranes leading to cytotoxicity or phospholipidosis, but may also contain information, not yet unraveled, on permeability. Surface activity measurements have also been used to make eshmates of oral absorphon [126]. 

Phospholipidosis is an excessive intracellular accumulation of phospholipids and drug, which is normally reversible after discontinuation of drug treatment. Currently, it is thought that phospholipidosis alone is not toxic per se, but because some compounds cause concurrent phospholipidosis and organ toxicity, avoidance of the issue in drug discovery projects seems prudent [74]. Fortunately, there are clear links between phospholipidosis and physical properties, especially lipophilicity, basicity, and amphiphilicity [75] which allow for good prediction of the risk. 

Inhibition of the hERG ion channel is firmly associated with cardiovascular toxicity in humans, and several drugs with this liability have been withdrawn. A number of studies show that basicity, lipophilicity, and the presence of aromatic rings [76] contribute to hERG binding. The 3D models of the hERG channel [77] are potentially useful to understand more subtle structure-activity relationships. In common with receptor promiscuity, both phospholipidosis and hERG inhibition are predominantly issues with lipophilic, basic compounds, and with the predictive models available, both risks should be well controlled. 

The drug is also a highly lipophilic base and accumulates in a number of tissues including the lung. This combination of extreme physicochemical properties can result in more specific interactions such as the condition of phospholipidosis (increase in total lung phospholipids) caused by inhibition of phospholipid breakdown [4]. The medicinal chemist has to decide if extreme lipophilicity and the presence of iodine are essential for activity and, in the case of amiodarone, proven clinical efficacy or whether alternative structures are possible. 

Very large VD values can be frequently associated with drugs that can exhibit phospholipidosis. It is important to note that this is not a cause and effect relationship, but a general trend. Furthermore, drugs that exhibit high tissue binding are difficult to remove by hemodialysis, in the event that a deleterious event, such as overdose, must be treated. 

Phospholipidosis (e.g., Nile red, lysotracker dyes, electron microscopy of lysosomal multilamellar bodies), vacuolization, autophagy, lysosomal uptake assays for cell viability (e.g., neutral red)... 

There are specific fiuorescent dyes for specific pathologies created by specific drug classes, such as phospholipidosis from cationic amphiphilic drugs [18, 19], mitochondrial DNA depletion by nucleoside reverse transcriptase inhibitors that also inhibit mitochondrial DNA polymerase gamma and redox cyclers that produce reactive oxygen species. The complex mechanism of statin-induced toxicity is demonstrated vith early sublethal effects on apoptosis, mitochondrial function and calcium homeostasis [20]. 

Biomarkers Translational safety biomarkers (e.g., mitochondrial toxicity can be detected in vitro and in vivo), phospholipidosis [37]... 

Morelli, J.K., Buehrle, M., Pognan, F., Barone, L.R., Fieles, W. and Ciaccio, P.J. (2006) Validation of an in vitro screen for phospholipidosis using a high-content biology platform. Cell Biology and Toxicology, 22 (1), 15-27. 

The result of this is accumulation of phospholipids, or phospholipidosis, in the tissues where accumulation of the drug occurs. Active uptake of a toxic compound into the target tissue may also occur. For example, the herbicide paraquat is actively accumulated in the lung, reaches toxic concentrations in certain cells, and then tissue damage occurs (see chap. 7). 

LuIIman H, LuIImann-Rauch R, Wassermann O, et al. Drug induced phospholipidosis. CRC Critical Rev Toxicol 1975 4 185-218. 

Drugs that cause phospholipidosis are cationic amphiphiles they contain a hydrophobic ring structure and a hydrophilic side chain with a positively charged amine group. Such chemicals can interact with either the ionic (e.g., chlorophentermine) or hydrophobic (e.g., amiodarone) moieties of phospholipids. 

The specific accumulation of phospholipids (phospholipidosis) can occur but it also occurs in other organs and tissues and will be discussed later in this chapter. 

It seems that for drugs to cause accumulation of phospholipids, the necessary physicochemical characteristic is the presence of both hydrophilic and lipophilic parts to the molecule, as exemplified by chlorphentermine (see chap. 3) (chap. 5, Fig. 1). They contain a hydrophobic ring structure and a hydrophilic side chain with a positively charged (cationic) amine group. Such molecules are known as cationic amphipathic drugs or CADs. Other drugs, all in use, known to cause phospholipidosis are amiodarone, chloroquine (chap. 5, Fig. 1), tafenoquine, and gentamycin. 

The clinical significance of phospholipidosis is related to secondary damage to tissue structure or impaired function possibly at the cellular level, for example, reduced immunological response. In the case of amiodarone, the phospholipidosis in the lung causes cough and breathing difficulties. 

Secondary events result from primary events, for example, changes in membrane structure/permeability, mitochondrial damage, and lysosomal destabilization. Tertiary events are final observable manifestations, for example, fatty change and phospholipidosis, apoptosis, blebbing, and necrosis. 

The drug binds to anionic phospholipids in the proximal tubule, may alter phospholipids metabolism, and cause phospholipidosis. Gentamycin also damages the hair cells in the ear. 

Laurent G, Kishore BK, Tulkens PM. Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem Pharmacol 1990 40 2383. 

Studies have been performed to elucidate the molecular basis of drug-induced phospholipidosis. It has been found that, in the case of drugs of the chlorphenter-... 

Another class of catamphiphilic drugs with high toxic potential is the aminoglycosides. Their nephrotoxicity is manifested by lethal injury to the proximal tubular cells by means of the induction of renal cortical lysosomal phospholipidosis. The toxic effect involves three steps the uptake of the antibiotics into the cells, the intralysoso-mal lipid storage, and, finally, cell necrosis. The aminoglycosides are highly water... 

Aleo MD, Navetta KA, Emeigh Hart SG et al. (2002) Mechanism-based urinary biomarkers of aminoglycoside-induced phospholipidosis. Comp Clin Pathol 11 193-194 de Mendoza SG, Kashyap ML, Chen CY, Lutmer RF (1976) High density lipoproteinuria in nephrotic syndrome. Metabolism 25 1143-1149... 

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