Many antiviral drugs (e.g., fialuridine; FIAU) produce clinically significant
mitochondrial toxicity that limits their dosing or prevents their use in the clinic.
Human ENT1 (hENT1) is expressed on the mitochondrial membrane and this
expression may enhance the mitochondrial toxicity of nucleoside drugs such as
FIAU (Lai et al., 2004). However, the lethal mitochondrial toxicity of
fialuridine observed in the clinic was not predicted from preclinical toxicity
studies in rodents (rats and mice), even at doses that were 1000-fold greater
than that used in the human study. In fact, human ENT1 but not mouse Ent1
was expressed in the mitochondrial membrane, indicating that fialuridine can
get into human but not mouse mitochondria via ENT1. This observation has
been confirmed by hepatocyte studies. The mitochondrial uptake of fialuridine
was higher in human hepatocytes than that in mouse hepatocytes, and this
uptake could be reduced by an ENT inhibitor in human hepatocytes but not in
mouse hepatocytes (Lee et al., 2006). Species difference in transporters may
influence preclinical toxic species selection.
Adefovir and cidofovir are clinically important antiviral agents and have
been shown to cause drug-associated nephrotoxicity in some patients.In vitro
studies demonstrated that adefovir and cidofovir were about 500 and 400-fold
more cytotoxic, respectively, in OAT1-transfected CHO cells compared to the
vector control transfected CHO cells, suggesting that the drug associated
nephrotoxicity could be caused by OAT1-mediated accumulation of adefovir
and cidofovir in renal proximal tubules (Ho et al., 2000).
6.3 Transporters in Drug Resistance
To date, three major mechanisms of drug resistance in cells have been identified
by using cellular and molecular biology techniques: first, decreased uptake of
water-soluble drugs such as folate antagonists, nucleoside analogues, and
cisplatin, which require transporters to enter cells; second, various changes in
cells that affect the capacity of cytotoxic drugs to kill cells, including alterations
in cell cycle, increased repair of DNA damage, reduced apoptosis and altered
metabolism of drugs; and third, increased energy-dependent efflux of
hydrophobic drugs that can easily enter the cells by diffusion through the
plasma membrane (Szakacs et al., 2006). Among these mechanisms, both
uptake (the first one) and efflux (the third one) processes are involved in
transporters. Drug resistance due to MDR1/P-gp has not been overcome yet in
the oncology arena to prevent remission of cancer. Overexpression of P-gp
in tumors can confer two orders of magnitude of resistance for drugs that are
P-gp substrates (Beketic-Oreskovic et al., 1995; Szakacs et al., 2006).
Combination therapy with transporters inhibitors, like verapamil, PSC 833,
GF120918 and cyclosporine, has offered some help against some refractory
tumors (Beketic-Oreskovic et al., 1995; Szakacs et al., 2006). Such inhibitors in
in vitrocell lines have markedly sensitized them to chemoagents. However, the
clinical benefit from those P-gp modulators is still a question (Szakacs et al., 2006).
154 DRUG TRANSPORTERS IN DRUG DISPOSITION, DRUG INTERACTIONS