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Drug-Induced Phospholipidosis: Prediction, Detection, and Mitigation Strategies

Part of the Topics in Medicinal Chemistry book series (TMC,volume 9)

Abstract

In the fast-paced and resource-intensive process of the discovery and development of novel medicines, issues pertaining to safety often appear leading to a loss of valuable resource and time for the pharmaceutical industry. Drug-induced phospholipidosis (DIPL) is one such issue that often shows up late in the discovery process, especially after repeat-dose toxicity studies in animals. DIPL is long debated as to whether it is a manifestation of toxicity or just an adaptation response due to drug accumulation in a tissue. Irrespective of the argument on either side, the conservative approach is to avoid DIPL due to closely associated toxicities and pathological similarity with phospholipid storage disorders. Therefore, high importance is given to predict the potential of a novel drug compound/series and to identify/confirm their potential to induce phospholipidosis (PLD) to help steer structure-activity relationship (SAR) to avoid this potential early in discovery. Several drugs with similar physicochemical properties are known to cause PLD, and these are generally referred to as cationic amphiphilic drugs (CADs). Using these known CADs, several in silico, in vitro, and hybrid methods have been developed to predict the potential to induce PLD. Also, a few biomarkers have shown promise of being able to monitor for DIPL during an ongoing animal study without the need to confirm PLD in tissues from necropsy. Early prediction, detection, and mitigation strategies are of immense value in developing novel medicines without PLD-inducing potential.

Keywords

  • Drug-induced phospholipidosis
  • Cationic amphiphilic drugs
  • lysosomes
  • toxicity
  • drug discovery

An erratum to this chapter can be found at http://dx.doi.org/10.1007/7355_2014_73

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Abbreviations

5-HT1B :

5-Hydroxytryptamine 1B

BMP:

bis(monoacylglycero)phosphate

CAD:

Cationic amphiphilic drug

Cell lines cited:

HepG2, ARLJ301-3, CHO-K1, CHL/IU, J744A, HuH7, rat hepatocytes

ClogP :

Calculated logarithm of the octanol–water partition coefficient

CMC:

Critical micelle concentration

DIPL:

Drug-induced phospholipidosis

DPP-IV:

Dipeptidyl peptidase IV

Genes cited:

MGC4171, NR0B2, INHBE, P8, SERPINA3, ASNS, C10, FLJ10055, FRCP1, AP1S1, TAGLN

H3R:

Histamine 3 receptor

hERG:

Human ether-a-go-go-related gene

K d :

Dissociation constant

LBPA:

Lyso-bis-phosphatidic acid

LDA:

Linear discriminant analysis

NBD-PC:

7-Nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-phosphatidylcholine

NBD-PE:

7-Nitrobenz-2-oxa-1,3-diazol-4-yl (NBD)-phosphatidylethanolamine

NC:

Net charge

PAG:

Phenylacetylglycine

pKa:

Logarithm of the acidic ionization constant

pKa-MB:

Logarithm of the ionization constant-most basic

PLA2:

Phospholipase A2

PLD:

Phospholipidosis

QSAR:

Quantitative structure-activity relationships

QT:

Beginning of the QRS complex to the end of the T wave in the electrocardiogram

SAR:

Structure-activity relationships

SMARTS:

Smiles arbitrary target specification

Softwares/programs cited:

ADMET, CAFCA, MC4PC, MDL-QSAR, Weka

TEM:

Transmission electron microscopy

TRI:

Triple reuptake inhibitor

Vd:

Volume of distribution

ΔΔGAM :

Free energy of amphiphilicity

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Acknowledgements

The authors greatly appreciate John Megill, Yang Wu, Donald Robertson, Discovery Toxicology, and Michele Agler, Lead Discovery, BMS, for providing the electron micrographs, leukocyte Nile Red staining data, urine BMP data, and Huh7 LipidTox staining data, respectively.

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Correspondence to Alicia Regueiro-Ren .

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Hanumegowda, U.M., Regueiro-Ren, A. (2013). Drug-Induced Phospholipidosis: Prediction, Detection, and Mitigation Strategies. In: Meanwell, N. (eds) Tactics in Contemporary Drug Design. Topics in Medicinal Chemistry, vol 9. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_34

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