Why we should be vigilant: drug cytotoxicity observed with in vitro transporter inhibition studies.

Article Details

Citation

Copy to clipboard

Zheng X, Diao L, Ekins S, Polli JE

Why we should be vigilant: drug cytotoxicity observed with in vitro transporter inhibition studies.

Biochem Pharmacol. 2010 Oct 1;80(7):1087-92. doi: 10.1016/j.bcp.2010.06.012. Epub 2010 Jun 23.

PubMed ID

20599790 [ View in PubMed

]

Abstract

From routine in vitro drug-transporter inhibition assays, observed inhibition is typically assumed from direct interaction with the transporter. Other mechanisms that possibly reduce substrate uptake are not frequently fully examined. The objective of this study was to investigate the association of transporter inhibition with drug cytotoxicity. From a pool of drugs that were identified as known ASBT or OCTN2 inhibitors, 21 drugs were selected to screen inhibitory potency of their prototypical substrate and cytotoxicity against three human sodium-dependent solute carrier (SLC) transporters: apical sodium-dependent bile acid transporter (ASBT), organic cation/carnitine transporter (OCTN2), and the excitatory amino acid transporter 4 (EAAT4) in stable cell lines. Twenty drugs showed apparent inhibition in OCTN2-MDCK and ASBT-MDCK. Four dihydropyridine calcium channel blockers were cytotoxic to MDCK cells, and the observed cytotoxicity of three of them accounted for their apparent OCTN2 inhibition, and consequently were classified as non-OCTN2 inhibitors. Meanwhile, since their cytotoxicity only moderately contributed to ASBT inhibition, these three were still considered ASBT inhibitors. Four other drugs showed apparent inhibition in EAAT4-HEK cells, and cytotoxicity of three drugs corresponded with their inhibition of this transporter. Therefore, cytotoxicity significantly affected EAAT4 observations. Results showed the potential of cytotoxicity as a mechanism that can account for apparent in vitro transporter inhibition. Drug cytotoxicity varied in different cell lines, which could increase false positives for pharmacophore development.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Levamlodipine	Ileal sodium/bile acid cotransporter	Protein	Humans	Unknown	Inhibitor	Details
Levamlodipine	Solute carrier family 22 member 5	Protein	Humans	Unknown	Inhibitor	Details