CLINICAL RELEVANCE: DRUG–DRUG INTERACTION,PHARMACOKINETICS,PHARMACODYNAMICS, AND TOXICITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 806

instance, the lipophilic HMG-CoA reductase inhibitors lovastatin and simvastatin,
which present a carboxylic acid moiety and are used clinically for the treatment
of hypercholesterolemia and mixed dyslipidemia, have been suspected to be MCT1
substrate drugs. In particular, it has been suggested that MCTs (especially, MCT1)
may contribute to the transport of simvastatin across the blood-brain barrier into the
brain, thus determining some of the CNS side effects (predominantly sleeplessness)
associated with the intake of these drugs. In vivo brain perfusion studies confirm
that penetration of these drugs across the blood-brain barrier correlates with these
side effects, and in vitro studies reported a possible role of MCT1 in the uptake of
simvastatin. 820 , 821 A possible contribution of MCTs to the intestinal absorption of
atorvastatin, another HMG-CoA reductase inhibitor, has been speculated, but other
mechanisms and/or transporters may be involved as well. 822
Drug-Drug Interactions To date, no clinically relevant drug-drug interactions me-
diated by MCTs have been described. However, because MCTs are involved in impor-
tant pathophysiological conditions (hypoglycemia, diabetes, starvation, cerebral and
heart ischemia), modulation of MCTs expression and activity may be a useful strategy
to protect some tissues from ischemic or metabolic damage. Recently, transfection
of MCT2 in cultured neurons has been reported to confer neuroprotection against
toxicity. 856 , 857 Further studies need to be undertaken to unravel the role of MCTs in
clinically relevant drug-drug interactions.
24.6. INTERACTIONS MEDIATED BY THE
NUCLEOSIDE TRANSPORTERS
Impact of Polymorphism on Function Recently, genetic variability in nucleoside
transporter family members have been described, although no pathophysiological
conditions have been associated with this family to date. However, large interindi-
vidual differences in response to anticancer and antiviral nucleoside analogs and
substrates of nucleoside transporters have been observed, suggesting that genetic
variability in nucleoside transporters could lead to reduced function or nonfunc-
tional transporter proteins. This could result in interpatient variability in systemic
and intracellular levels of nucleoside analog drugs. In general, equilibrative nucle-
oside transporters (ENTs) appear to have less genetic and functional diversity than
do concentrative nucleoside transporters (CNTs). No significant differences in the
functional characterization were found between the two recently identified nonsyn-
onymous variants of ENT1 and the reference ENT1. 858 Five protein-altering variants
were identified for ENT2, but they were found at very low frequency, making the
hypothesis unlikely that genetic variation of ENT2 significantly affects the variability
in drug response that is observed clinically. 859
Regarding the CNT family, CNT1 and CNT2 display more genetic diversity than
CNT3. Recently, Gray et al. have observed in an ethnically diverse population a high
degree of genetic and functional variation in CNT1. In particular, two nonfunctional
variants and one variant (CNT1-Val189Ile) with reduced affinity for the anticancer