Premium
Biopharmaceutical characterization of a novel sustained‐release formulation of allopurinol with reduced nephrotoxicity
Author(s) -
Nihei Takuya,
Sato Hideyuki,
Onoue Satomi
Publication year - 2021
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.2260
Subject(s) - allopurinol , biopharmaceutical , nephrotoxicity , pharmacology , pharmacokinetics , chemistry , medicine , kidney , microbiology and biotechnology , biology
The present study was aimed to develop a novel sustained‐release formulation for allopurinol (ALP/SR) with the use of a pH‐sensitive polymer, hydroxypropyl methylcellulose acetate succinate, to reduce nephrotoxicity. ALP/SR was evaluated in terms of crystallinity, the dissolution profile, pharmacokinetic behavior, and nephrotoxicity in a rat model of nephropathy. Under acidic conditions (pH1.2), sustained release behavior was seen for ALP/SR, although both crystalline ALP and ALP/SR exhibited rapid dissolution at neutral condition. After multiple oral administrations of ALP samples (10 mg‐ALP/kg) for 4 days in a rat model of nephropathy, ALP/SR led to a low and sustained plasma concentration of ALP, as evidenced by half the maximum concentration of ALP and a 2.5‐fold increase in the half‐life of ALP compared with crystalline ALP, possibly due to suppressed dissolution behavior under acidic conditions. Repeated‐dosing of ALP/SR resulted in significant reductions in plasma creatinine and blood urea nitrogen levels by 73% and 69%, respectively, in comparison with crystalline ALP, suggesting the low nephrotoxic risk of ALP/SR. From these findings, a strategic SR formulation approach might be an efficacious dosage option for ALP to avoid severe nephrotoxicity in patients with nephropathy.