| Xenobiotic excretion of drugs is a function of the kidneys. The isolated perfused kidney (IPK) is an advantageous method to study renal excretion, providing a system in which renal excretion can be studied without any other organs contributing to the metabolism or excretion of the dosed drug. Various transporters that mediate xenobiotic excretion are localized in the kidney. The IPK method also provides a way to probe the role of transporters in the excretion of various drugs. Cytarabine is a nucleoside analog that is used in the treatment of cancer, mainly for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).;In this research, cytarabine excretion was studied in the IPK system at a clinically relevant dose, the perfusate concentration was 2 mug/mL. Cytarabine protein binding in perfusate was tested using an ultrafiltration method. The fraction unbound (fu) was shown to be 0.86. The renal clearance of cytarabine was 0.51 mL/min. The net mechanism of excretion was reabsorption. The renal excretion in the presence of the organic cation transporter (OCT) inhibitor cimetidine was increased. The renal excretion in the presence of probenecid (an OAT inhibitor) did not change. The renal excretion of other anticancer drugs (gemcitabine, clofarabine, nelarabine, and fludarabine) was also compared to that of cytarabine. The renal excretion ratio (XR) of all compounds showed net reabsorption except for clofarabine. Although these medications have slightly different mechanisms of action and chemical structures, they showed similar excretion mechanisms. |
