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

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

Volume: 13 Issue: 3

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

Affiliation:

• The First Affiliated hospital, College of Medicine, Zhejiang University, 79 QingChun Road, Hangzhou, Zhejiang 310000,China

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

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.

Cite this article as:

Zheng Jinqi , Hu Haihong , Liu Lin , Rao Yuefeng , Lou Yan *, Zeng Su , An Impurity in Tenofovir Disoproxil Fumarate Exhibits High Human Organic Anion Transporter 1 Dependent Cytotoxicity, Current Pharmaceutical Analysis 2017; 13 (3) . https://dx.doi.org/10.2174/1573412912666160524121837

DOI https://dx.doi.org/10.2174/1573412912666160524121837	Print ISSN 1573-4129
Publisher Name Bentham Science Publisher	Online ISSN 1875-676X