Peramivir was a novel and highly potent
neuraminidase (NA) inhibitor for the treatment of
influenza A and B. However, it exhibited a very low oral bioavailability (only 3%) due to the high polarity (log P of -1.4) and the low membrane permeability across the intestine. To utilize the PEPT1-mediated
prodrug strategy to improve the oral absorption and develop the oral alternative, seven
amino acid ester prodrugs and seven
amino acid amide prodrugs have been synthesized. The permeability of these
prodrugs across Caco-2 cells were screened. Peramivr-(CH2)2-l-Val and
Peramivir-l-Ile were of the highest permeability in
ester prodrugs and
amide prodrugs, respectively, and then they were selected for further studies.
Glycylsarcosine (
gly-sar) uptake by Caco-2 could be inbihited by Peramivir-(CH2)2-l-Val and
Peramivir-l-Ile in a concentration-dependent manner, and the IC50 was 1.34 ± 0.31 mM and 1.78 ± 0.48 mM, respectively. The direct uptake of Peramivir-(CH2)2-l-Val and
Peramivir-l-Ile in MDCK-PEPT1 cells were significantly higher than in MDCK mock cells, and could be markedly inhibited by
gly-sar. The uptake of Peramivir-(CH2)2-l-Val and
Peramivir-l-Ile (0.01 to 50 mM) in MDCK-hPEPT1 cells conformed to Michaelis-Menten Equation. The oral bioavailability of
peramivir was 65.3% and 37.3% after the
oral administration of Peramivir-(CH2)2-l-Val and
Peramivir-l-Ile to rats, respectively. The oral absorption and bioactivation of Peramivir-(CH2)2-l-Val was rapid and extensive, and no Peramivir-(CH2)2-l-Val was found in plasma. Because the
amide bond was relatively stable,
Peramivir-l-Ile could not be totally converted to the parent drug in vivo. Peramivir-(CH2)2-l-Val with good oral profiles and rapid bioactivation might be a promising
prodrug for the further clinic development. The present study also corroborated the idea that the PEPT1-mediated
prodrug approach has enormous promise for improving the oral absorption of poorly absorbed drug.