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In Vitro Evaluation of Absorption Characteristics of Peramivir for Oral Delivery

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European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Peramivir is a novel antiviral agent approved for the treatment of severe influenza. However, the development of oral formulation of peramivir has been severely hurdled by poor bioavailability (human, ≤3%). The present work aims to evaluate oral permeability characteristics of peramivir.

Methods

In vitro gastrointestinal stability, metabolic stability in human intestinal S9 fraction and Caco-2 permeability were performed. The liquid chromatography with tandem mass spectrometric (LC–MS/MS) was used to quantify peramivir in buffer and biological sample. Using GastroPlus™ software, intestinal effective permeability coefficient (P eff) of peramivir was estimated.

Results

Our results indicated that peramivir maintained stability in pH 5.5 and 7.4 buffers, fasted state simulated gastric fluid and fasted state simulated intestinal fluid, and human intestinal S9 fractions. The apparent permeability coefficient (P app) values of peramivir (10 μM) were 3.29 ± 0.73 × 10−7 cm/s in a Caco-2 cell model. In vivo intestinal effective permeability coefficient (P eff) was estimated to be 0.06 × 10−4 cm/s. Furthermore, co-incubating with cyclosporine, mitoxantrone, rifampicin, or paroxetine, the apical (AP) to basolateral (BL) flux of peramivir decreased (p < 0.05). The efflux and influx of peramivir was not significantly affected with co-incubation with verapamil, MK-571, or diclofenac (p > 0.05).

Conclusions

These results revealed that carrier-mediated transports, including OATP1B (organic anion transport 1B) and OCT1 (organic cation transport 1), might be involved in the absorption of peramivir. In conclusion, our results provide insight into the poor oral bioavailability of peramivir. Peramivir can be classified as a BCS-III (high solubility/low permeability) and BDDCS-III high solubility/poor metabolism) drug. The oral bioavailability of peramivir primarily depends on its permeability across cell membranes. Both of passive and active transports are involved in the permeability of peramivir.

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Acknowledgements

This project was supported by Beijing Natural Science Foundation (7162148) and the National Natural Science Foundation of China (81573357, 81102498).

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Authors and Affiliations

  1. Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, 100850, China

    Ying Li, Zhiyuan Wang, Wei Gong, Yang Yang, Wu Zhong & Aiping Zheng

  2. Department of Pharmacy, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China

    Xin Li

  3. Department of Pharmacy, Wuhan General Hospital of Guangzhou Military Command, 627 Wuluo Road, Wuchang District, Wuhan, 430070, China

    Xiangyang Xie

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  1. Ying Li
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  2. Zhiyuan Wang
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Correspondence to Ying Li.

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Conflict of interest

All of authors (Ying Li, Zhiyuan Wang, Xin Li, Wei Gong, Xiangyang Xie, Yang Yang, Wu Zhong and Aiping Zheng) have no conflicts of interest.

Additional information

W. Zhong and A. Zheng are co-corresponding authors.

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Li, Y., Wang, Z., Li, X. et al. In Vitro Evaluation of Absorption Characteristics of Peramivir for Oral Delivery. Eur J Drug Metab Pharmacokinet 42, 757–765 (2017). https://doi.org/10.1007/s13318-016-0390-x

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