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Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

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Abstract

The purpose of this study was to characterize the disposition, distribution, excretion and plasma protein binding of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1) in rats. Concentrations of W-1 within biological samples were determined using a validated high performance liquid chromatography method. The plasma protein binding of W-1 was examined by equilibrium dialysis method. After oral administration of W-1 (50, 100 and 200 mg/kg, respectively) in self-microemulsifying drug delivery system formulation, the pharmacokinetic parameters of W-1 were as follows: the peak plasma concentrations (C max) were 0.42, 1.50 and 2.55 μg/mL, the area under the curve (AUC0−t) were 0.89, 2.27 and 3.96 µg/h mL and the plasma half-life (t 1/2) were 5.15, 3.77 and 3.77 h, respectively. Moreover, the prototype of W-1 was rapidly and extensively distributed into fifteen tissues, especially higher concentrations were detected in intestine, stomach and liver, respectively. The plasma protein binding of W-1 in rat, beagle dog and human were in the range of 97.96–99.13 %. This study suggested that W-1 has an appropriate pharmacokinetics in rats, such as rapid absorption, moderate clearance, and rapid distribution to multiple tissues. Those properties provide important information for further development W-1 as an anti-HIV-1 drug candidate.

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Acknowledgments

This study was supported by the National Natural Science foundation of China (91029747, 81330074 and 81473276) and National Basic Research Program of China (2015CB932100).

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Authors and Affiliations

  1. Department of Pharmacology, School of Basic Medical Science, Beijing (Peking) University, No.38, Xue-Yuan Road, Beijing, 100191, People’s Republic of China

    Ying-Yuan Lu, Xin Wang, Pu Li, Ya-Qing Lou & Guo-Liang Zhang

  2. Department of Chemical Biology, School of Pharmaceutical Sciences, Beijing (Peking) University, Beijing, 100191, People’s Republic of China

    Xiao-Wei Wang & Jun-Yi Liu

  3. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Beijing (Peking) University, Beijing, 100191, People’s Republic of China

    Wen-Bing Dai & Qiang Zhang

  4. Department of Drug Metabolism & Pharmacokinetics, Biogen, MA, USA

    Chuang Lu

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  1. Ying-Yuan Lu
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Correspondence to Guo-Liang Zhang.

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Lu, YY., Wang, XW., Wang, X. et al. Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats. Arch. Pharm. Res. 39, 970–977 (2016). https://doi.org/10.1007/s12272-016-0727-7

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