S. Kurtz, James E. Fitzgerald, J. Schardein
May 1, 1977
Citations
0
Influential Citations
11
Citations
Journal
Annals of the New York Academy of Sciences
Abstract
Vidarabine (ara-A) has been studied extensively by Parke, Davis & Company for about 10 years. Its poor solubility (about 0.5 mg/ml) was recognized as a clinical liability very early in the decision to develop its therapeutic indication, and, although several soluble derivatives had been produced in the laboratory, production cost considerations dictated that we pursue vidarabine as our primary candidate. With time and experience, the 5‘-monophosphate became available in adequate quantity, and it was designated as the second generation soluble agent. We undertook basic laboratory studies to compare the antiviral activity, toxicology, and metabolism of the native vidarabine with its soluble metabolite, ara-AMP (5’-monophosphate). It should be kept in mind that, because of solubility differences, the parenteral routes utilized were not always the same with both compounds. Furthermore, because of our initial ignorance regarding the metabolism of ara-AMP, we elected to consider it to be 100% active moiety, and all doses were calculated on that basis. Subsequent metabolic studies indicated that the phosphate should not be included in calculating activity. Therefore, the true biologically active doses of ara-AMP are actually about 25% lower than the stated values in this presentation. Except when indicated, the work reported in this presentation was done at Parke, Davis & Company Research Laboratories, and is documented in reports filed there and with the U.S. Food and Drug Administration.