Biomedical Engineering Reference
In-Depth Information
coadministration of celecoxib enhanced the antitumor activity of irinotecan and re-
duced the gastrointestinal side effects in mice bearing HT-29 and colon-26 tumor.
One of the possible mechanisms involved in this beneficial drug-drug interaction
might be the modulation of MRP4 function, but further studies are needed to explore
the role of MRP4 in resistance, toxicity, and pharmacokinetics of irinotecan and its
metabolites.
493
To date, several clinical phase I/II studies exploring the efficacy and
safety of the association of irinotecan and celecoxib, frequently in combination with
other drugs (e.g., docetaxel, 5 fluorouracil/leucovorin, thalidomide), in colorectal
cancer, lung cancer, and malignant glioma have been performed, but the results are
inconclusive.
494
-
499
The multidrug resistance proteins
MRP5
to
MRP9
have not yet been completely
characterized. Thus, their physiological and pharmacological role and possible in-
volvement in drug-drug interactions are not clear at this moment.
24.3. INTERACTIONS MEDIATED BY ORGANIC ANION
AND CATION TRANSPORTERS
24.3.1. Organic Anion Transporters
Impact of Polymorphism on Function
Genetic variation in OATs has been studied
in several different populations, but currently little is known about the impact of these
genetic variants on drug disposition, toxicity, and disease.
500
,
501
A total of 25 single-
nucleotide polymorphisms (SNPs) were identified from OAT1-OAT3 gene loci in
healthy Japanese volunteers and involved the 5
flanking regions, the 5
untranslated
regions, the coding regions, and introns, but their functional consequences were not
explored.
502
More recently, SNPs in OAT family members were analyzed in an eth-
nically diverse sample of 96 individuals as well as combinations of OATs1 to 4 and
URAT1 in particular ethnic groups. A total of 29 SNPs were identified, 14 of which
were nonsynonymous and most of which were located in the OAT4 gene. Subjects
with nonsynonymous SNPs in OATs localized in both apical and basolateral mem-
branes, as well as with combinations of synonymous SNPs in OAT1 and OAT3, were
found. Certain ethnic groups displayed a high prevalence of nonsynonymous SNPs in
particular OATs (such as OAT4 in sub-Saharan Africans), and this finding may sup-
port the hypothesis of an association between ethnic group and risk to develop toxic
and adverse drug reactions to several commonly prescribed drugs.
501
Furthermore,
polymorphism in OAT4 has been suggested to potentially affect the fetal in utero risk
because of toxicity by endogenous and/or exogenous compounds.
501
Recently, sequencing of the SLC22A12 gene in 32 Japanese subjects affected by
idiopathic renal hypouricemia, it was demonstrated that URAT1 was responsible for
most cases of renal hypouricemia, especially severe renal hypouricemia. In these
Japanese patients, eight new mutations and two previously identified mutations of
SLC22A12 gene were found, resulting in loss of URAT1 function and clinically re-
nal hypouricemia. In particular mutation G774A, changing tryptophan 258 (TGG)
to a stop codon (TGA) and resulting in a truncated nonfunctional URAT1 protein,
which was associated with the development of hypouricaemia, was reported as the
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