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

Abstract

Purpose: To compare the potential metabolism and protein binding interactions with selected camptothecin agents. Methods: Cytochrome P450 (CYP450) isoenzymes were used to screen and predict the enzymes involved in metabolism of each selected Camptothecin agent. Known substrates and inhibitors of each isoenzyme were used to predict drug interactions with the camptothecin agents. The effects of both albumin (Alb) and alpha-acidic glycoprotein (AAG) on plasma protein binding (PPB) for each camptothecin was assessed by equilibrium dialysis techniques in the presence of varying ratios of Alb and AAG. Results: Karenitecin is metabolized by CYP3A4, 2D6, 2C8, and 2C9 and is an inhibitor of the 2D6 and 2C8 isoenzymes. Topotecan was primarily metabolized by 3A4 but also by 2D6 and 2C9. Irinotecan was similar to the parent compound, camptothecin, in its ability to inhibit 2D6 as well as being a substrate for 3A4. The mean percent protein bound was >85% for all agents evaluated with the exception of Topotecan whose protein binding was low yet highly variable with alterations in plasma protein concentration. The extent of camptothecin plasma protein binding was proportional to the plasma concentration of AAG. Conclusion: The camptothecin agents have the potential for 3A4, 2C9, and 2C8 drug interactions that should be monitored prospectively to avoid toxicity. In addition, slight variations in plasma AAG and Alb concentration could result in large variations in free drug exposure and potentially contribute to increased toxicity. This should be monitored when employing combination chemotherapy with camptothecin agents.