Ying Li1, Zhiyuan Wang2, Xin Li3, Wei Gong2, Xiangyang Xie4, Yang Yang2, Wu Zhong2, Aiping Zheng2. 1. Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, 100850, China. liying.sky@126.com. 2. Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Beijing, 100850, China. 3. Department of Pharmacy, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853, China. 4. Department of Pharmacy, Wuhan General Hospital of Guangzhou Military Command, 627 Wuluo Road, Wuchang District, Wuhan, 430070, China.
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.
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.
Entities:
Keywords:
Breast Cancer Resistance Protein; Influenza; Oseltamivir; Paroxetine; Zanamivir
Authors: Thorir D Bjornsson; John T Callaghan; Heidi J Einolf; Volker Fischer; Lawrence Gan; Scott Grimm; John Kao; S Peter King; Gerald Miwa; Lan Ni; Gondi Kumar; James McLeod; R Scott Obach; Stanley Roberts; Amy Roe; Anita Shah; Fred Snikeris; John T Sullivan; Donald Tweedie; Jose M Vega; John Walsh; Steven A Wrighton Journal: Drug Metab Dispos Date: 2003-07 Impact factor: 3.922
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