Enhanced chemical stability of the intracellular prodrug, 1-[(( S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine, relative to its parent compound, cidofovir

• Published in: International journal of pharmaceutics Vol. 179; no. 2; pp. 257 - 265
• Main Authors: Oliyai, Reza, Lee, William A, Visor, Gary C, Yuan, Lung-Chi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 15-03-1999; Elsevier
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Biological and medical sciences; Chemical stability; Cidofovir; Cyclic HPMPC; Cytosine; Cytosine - analogs & derivatives; Cytosine - chemistry; Deamination; Drug Stability; Hydrolysis; Kinetics; Medical sciences; Organophosphonates; Organophosphorus Compounds - chemistry; Pharmacology. Drug treatments; Prodrug; Prodrugs - chemistry; Solubility; Cidofovir; Cytosine; Prodrug; Deamination; Chemical stability; Cyclic HPMPC; Cytosine derivatives; Reaction mechanism; Antiviral; Chemical degradation; Comparative study
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/S0378-5173(98)00395-0

Degradation kinetics of cyclic HPMPC (cHPMPC), 1-[((
S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine, and its parent compound cidofovir (also known as HPMPC) were conducted in the pH range of 2–11 at 70°C. cHPMPC manifested greater chemical stability than cidofovir, except under alkaline conditions (pH>9). Three degradation products—cidofovir, cyclic HPMPU and HPMPU—were identified for cHPMPC, and the product distribution was characterized via a stability-indicating HPLC assay. Cyclic HPMPU and HPMPU are the uracil analogs of cHPMPC and cidofovir, respectively, formed through a hydrolytic deamination pathway. The deamination and hydrolysis rate constants for cHPMPC under acidic conditions were derived from the degradation product curves. The deamination rate constants for cHPMPC were about 8-fold slower compared to that for cidofovir. The enhanced chemical stability for cHPMPC relative to cidofovir is attributed to the absence of intramolecular catalysis with cHPMPC.