Evaluation of Ion-pair Formation of Adefovir to Improve Permeation across Artificial and Biological Membranes

Bahar Darsazan1, Alireza Shafaati2, Afshin Zarghi2, Seyed Alireza Mortazavi1

1Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
2Department of Pharmaceutical Chemistry School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.


Purpose: Adefovir is an antiviral drug that exhibits high hydrophilic properties and negligible bioavailability (less than 12%). It is only applied in the form of the ester prodrug adefovir dipivoxil (ADV). The oral bioavailability of ADV is limited (32% to 45%) by its low permeability (Class 3) and biological conversion of the prodrug to adefovir. Ion-pair formation is considered as an alternative approach to a covalent prodrug (ADV) to enhance intestinal permeation of adefovir. Methods: The effect of various counter-ions (anionic, cationic and two quaternary ammonium salts) on the lipophilicity of adefovir was investigated by means of the n-octanol/buffer partitioning system, an in vitro transport model (PAMPA) and a biological membrane (everted gut sac). Results: Quaternary ammonium salts, cetylpyridinium chloride (CPC) and cetrimide enhanced the lipophilicity of adefovir 136- and 87-fold, respectively. The apparent permeability of adefovir in combination with CPC (counter-ion) was 2.5-fold greater than ADV permeability in the PAMPA model. The apparent permeability of adefovir-CPC (counter-ion) was 1.3-fold greater than that of adefovir dipivoxil permeability in a biologic membrane (everted gut sac). Conclusion: These results suggest that the adefovir-CPC ion-paired system has potential for improving the permeation of adefovir across the intestinal membrane.


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J Pharm Pharm Sci, 21 (1): 160-170, 2018

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DOI: http://dx.doi.org/10.18433/jpps29394