Evaluation of Potential Cytochrome P450 and Plasma Protein Binding Drug Interactions for the Class of Camptothecins

Camptothecin were first introduced in the early 1970’s, formulated in sodium hydroxide to enhance solubility, in clinical trials but was terminated due to a lack of clinical antitumor activity and a significant incidence of hemorrhagic diarrhea and uroepithelial toxicity [1]. These unexpected toxicities are believed to have been due to instability of camptothecin, which exists as biologically inactive carboxylate salts in solution [2]. In general, the development of camptothecin derivatives has been fraught with problems associated with the significant and unpredictable variability in the pharmacokinetics and pharmacodynamics of these compounds. This has been attributed to the limited water solubility of these drugs, variances in their metabolism and the relative instability of the active lactone form of these compounds mentioned [3].