CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 809

down-regulate the M-CSF-induced expression of ENT1. 910 , 912 In addition, hormonal
regulation of nucleoside transporters has been reported in various tissues and cell
types. In a study using rat liver, glucagon was reported to up-regulate the nucleoside
transport, whereas insulin was able to stimulate Na + -dependent uridine uptake by
stimulation of synthesis of the transporters. 912 In cultures of rat B and T lymphocytes,
nucleoside transporter expression levels were reported to be regulated independently
and differentially by glucose and insulin. 913 , 914 Elevated levels of glucose were also
reported to induce the expression of ENT1 in human aortic smooth muscle cells. 915
High concentrations of glucose reduced the expression level and transport activity
of ENT1 and affected adenosine transport in human umbilical vein endothelial cells
(HUVECs) with a mechanism that involved endothelial nitric oxide synthase, PKC,
and MAP kinases. 916 , 917 The thyroid hormone T3 and dexamethasone were able to
induce selective up-regulation of CNT2 and down-regulation of ENT1 and ENT2 in
rat fetal hepatocytes. 918 T3 has also been reported to induce the expression of nucleo-
side transporters and to stimulate adenosine transport in cultured chromaffin cells. 919
Possible clinical implications of these findings need to be explored further.
Pharmacological and Toxicological Function The cellular location of nucleoside
transporters in several normal and cancer tissues and in organs, which play a key role
in drug distribution, suggest that they may influence the intracellular bioavailability
and the pharmacokinetic, therapeutic, and toxicological profiles of affected nucleoside
analog substrate drugs. Variation in nucleoside transporter expression may contribute
to variation in drug efficacy and drug resistance: Transport of nucleoside analogs
is the first step in tumor cytotoxicity. In general, tumors display highly variable
patterns of ENT and CNT expression, which affects drug bioavailability and action.
Decreased nucleoside transporter expression and/or activity in tumor tissues and in
virally infected cells that are targets for nucleoside antiviral drugs have been correlated
with reduced drug-uptake and the development of drug resistance. Chemosensitivity
and ex vivo cytotoxicity of cytarabine, fludarabine, and other nucleoside analogs have
been correlated to expression of subtypes of nucleoside transporters in several in
vitro studies. 875 , 876 , 884 , 920 - 927 Furthermore, gemcitabine cytotoxicity was correlated
to nucleoside transporter activity in cell lines derived from a variety of lymphoid
and human pancreatic adenocarcinomas with defined different patterns of nucleoside
transporter expression. 868 , 875
The location of nucleoside transporters (in particular, CNTs) in the intestine, kid-
ney, and liver suggests that these transporters may affect the systemic absorption
and disposition of nucleoside analog substrate drugs. The significant expression of
CNT2 in the gastrointestinal tract is supposed to be a major factor in absorption of
orally administered ribavirin and other natural purine and purine analogs. 887 , 928 In
addition, the broad tissue distribution of ENT1 appears to be a major determinant
of the unusually large distribution volume of ribavirin. 867 , 929 Furthermore, the renal
disposition of natural nucleosides and nucleoside analogs appears to be affected by
nucleoside transporters widely expressed in the kidney. 930 In contrast, although some
nucleoside transporters have been found in brain capillary endothelial cells that form