Role of equilibrative nucleoside transporter 1 (ENT1) in the disposition of cytarabine in mice

Cytarabine (Ara‐C) is a nucleoside analog used in the treatment of acute myeloid leukemia (AML). Despite the many years of clinical use, the identity of the transporter(s) involved in the disposition of Ara‐C remains poorly studied. Previous work demonstrated that concurrent administration of Ara‐C with nitrobenzylmercaptopurine ribonucleoside (NBMPR) causes an increase in Ara‐C plasma levels, suggesting involvement of one or more nucleoside transporters. Here, we confirmed the presence of an NMBPR‐mediated interaction with Ara‐C resulting in a 2.5‐fold increased exposure. The interaction was unrelated to altered blood cell distribution, and subsequent studies indicated that the disposition of Ara‐C was unaffected in mice with a deficiency of postulated candidate transporters, including ENT1, OCTN1, OATP1B2, and MATE1. These studies indicate the involvement of an unknown NBMPR‐sensitive Ara‐C transporter that impacts the pharmacokinetic properties of this clinically important agent.