CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 807

pyrimidine nucleoside analog gemcitabine were described. 860 , 861 In addition, a non-
synonymous CNT2 variant (CNT2-F355S) with significant allelic frequency was
identified in the African-American population; it displayed altered specificity for
inosine and uridine. 860 In contrast, CNT3 has less genetic and functional diversity,
suggesting that CNT3 is more critical for viable human life, tolerating less genetic
and functional diversity. 858 Possibly, more genetic variation can be tolerated in CNT1
and CNT2, because together with CNT3, they display overlapping tissue distribution
and substrate specificity.

Main Substrate Classes (Clinically Applied) In general, most nucleosides, nucle-
obases, and their analogs used in anticancer and antiviral therapy are substrates of
the nucleoside transport systems. There are many similarities between the spectrum
of compounds transported by ENTs and CNTs, although there is no complete over-
lap. ENT1 displays broad substrate specificity for purine and pyrimidine nucleo-
sides, with higher affinity for adenosine and lower affinity for cytidine, but it is
reported not to transport nucleobases. 862 - 866 Anticancer and antiviral drugs trans-
ported by ENT1 include gemcitabine, cytarabine, fludarabine, cladribine, and rib-
avirin, whereas the nucleoside analogs 2 ,3 -dideoxycytidine (zalcitabine, ddC) and
2 ,3 -dideoxyinosine (didanosine, ddI) are only weak substrates. The antiviral drug
3 -azido-3 deoxythymidine (zidovudine, AZT) is reported not to be a substrate for
ENT1. 862 , 864 , 867 - 871
ENT2 transports a broad range of substrates, including purine and pyrimidine
nucleosides (although with a lower apparent affinity than ENT1, with the exception
of inosine), 863 , 864 , 872 nucleobases (hypoxantine, adenine, guanine, uracil, thymine,
and cytosine), 873 and possibly, cyclic nucleotides. 874 In contrast to ENT1, ENT2 can
transport AZT and displays much greater affinity for ddC and ddI. 864 , 870 Recently, it
has been reported that the anticancer drugs gemcitabine and fludarabine are substrates
of ENT2. 875 - 877
Characterization of the substrate specificity of ENT3 and ENT4 is currently in prog-
ress. ENT3 appears to be able to transport several nucleosides (with the exception of
hypoxantine) and antiviral nucleoside analogs such as AZT, ddC, and ddI. Adeno-
sine is reported to be a weak substrate for ENT4. 878 , 879 CNT1 selectively trans-
ports pyrimidine nucleosides (cytidine, thymidine, uridine) and adenosine. 880 , 881
CNT1 substrates also include the antiviral nucleoside analogs zidovudine (3 -
azido-3 -deoxythymidine, AZT), lamivudine (2 ,3 -dideoxy-3 -thiacytidine, 3TC),
zalcitabine (2 ,3 -dideoxycytidine, ddC), the anticancer drugs gemcitabine (2 ,2 -
difluorodeoxycytidine, dFdC), cytarabine [(1-

-D-arabinofuranosyl)cytosine, AraC],
and 5 -deoxy-5-fluorouridine (5 -DFUR, which is the active metabolite of
capecitabine). 869 , 880 , 882 - 884 In contrast, CNT2 transports purine nucleosides (adeno-
sine, guanosine, inosine), uridine, and formycin B selectively. 881 , 885 - 886 CNT2 sub-
strates also include didanosine (2 ,3 -dideoxyinosine, ddI) and ribavirin, 880 , 886 - 888
but CNT2 does not appear to transport other antiviral drugs, such as zidovu-
dine, zalcitabine, or the anticancer nucleoside analogs currently used in anticancer
chemotherapy. 870 , 886 , 888 CNT3 is widely selective for nucleoside substrates, accepting