An Impurity in Tenofovir Disoproxil Fumarate Exhibits High Human Organic Anion Transporter 1 Dependent Cytotoxicity

Author(s): Jinqi Zheng, Haihong Hu, Lin Liu, Yuefeng Rao, Yan Lou*, Su Zeng

Journal Name: Current Pharmaceutical Analysis

Volume 13 , Issue 3 , 2017

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Graphical Abstract:


Background: Tenofovir disoproxil fumarate (TDF) is an oral prodrug and a nucleotide analog used for treating human immunodeficiency virus (HIV) and hepatitis B virus (HBV). A growing subset of TDF-treated HIV(+) individuals experienced drug-associated acute renal failure, suggesting drug-related nephrotoxicity. Impurities in pharmaceutical drugs generally present a risk, and no obvious benefit.

Method: In an effort to determine whether the impurities also contribute to the nephrotoxicity, seven impurities were isolated and identified by using nuclear magnetic resonance (NMR) and mass spectra (MS). Human renal organic anion transporter 1 (hOAT1) localized in the kidney was the major transporter of tenofovir and presumably mediates its accumulation in the renal proximal tubules. On the basis of the Guidance for Industry document published by the United States Food and Drug Administration (U. S. FDA), we conducted an uptake assay and performed inhibition analysis using the Madin-Darby canine kidney cells stably expressing human OAT1 (MDCK-hOAT1), before analyzing our data by liquid chromatography tandem mass spectrometry (LC-MS/MS).

Results: The uptake of the newly detected impurity RS5 was significantly higher than that of TDF. The 3- (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay showed that RS5 was more cytotoxic than TDF. The structure-affinity relationships indicated that 9-methyl functioned as a detoxification group.

Conclusion: Our findings provide useful information for understanding the structure and toxicity of TDF and its impurities, and for assessing the clinical applications of TDF.

Keywords: Tenofovir disoproxil fumarate, impurity, NMR, cytotoxicity, MDCK-hOAT1, LC-MS/MS.

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Article Details

Year: 2017
Published on: 05 April, 2017
Page: [232 - 240]
Pages: 9
DOI: 10.2174/1573412912666160524121837
Price: $65

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