Biomedical Engineering Reference
In-Depth Information
Moreover, by potentially altering the physiologic protective role of Pgp, genetic
variation in ABCB1, has recently been assessed in the etiology of several human patho-
physiological conditions. An increasing number of studies have associated certain
SNPs in ABCB1 with susceptibility to such diseases as pharmacoresistant epilepsy,
Parkinson's disease, inflammatory bowel diseases (e.g., ulcerative colitis, Crohn's
disease), colorectal cancer, and renal carcinoma.
14
-
19
In addition, C3435T polymorphism has been linked to an increased immunological
response (CD4 count) to the anti-HIV protease inhibitor nelfinavir in HIV-positive
patients,
20
although some later studies confirmed and others contradicted the associa-
tion of certain ABCB1 SNPs with the efficacy of antiviral therapy in HIV patients.
21
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26
Recently, ABCB1 SNP C3435T has been associated with antiemetic treatment effi-
cacy with 5-hydroxytryptamine type 3 receptor antagonists (e.g., granisetron, on-
dansetron, tropisetron) in patients with cancer,
27
whereas in patients affected by
depression, the same polymorphism has been linked to the development of postural
hypotension induced by the antidepressant nortriptyline.
28
The 2677T SNP has been
recognized as a positive predictor of tacrolimus-induced neurotoxicity.
29
Furthermore,
in a recent study, hypercholesterolemic patients carrying the 1236T variant allele
showed higher lipid-lowering efficacy of simvastatin treatment than for homozygotes
with the wild-type allele. 1236T, 2677A/T, and 3435T alleles were also associated with
reduced incidence of adverse reaction to the 3-hydroxy-3-methylglutarylcoenzyme
A (HMG-CoA) synthase inhibitor simvastatin.
30
MDR1 gene polymorphism is also suggested to affect the outcome of patients
with several malignancies. Goreva et al. reported an association between C3435T and
G3677T SNPs in ABCB1 and the risk of drug resistance in patients with lympho-
proliferative diseases.
31
A correlation between several commonly occurring ABCB1
SNPs and overall survival and risk of relapse has been reported in patients affected
by acute myeloid leukemia treated with etoposide, mitoxantrone, or daunorubicin
(well-known Pgp substrates).
32
Moreover, ABCB1 SNP C3435T has been suggested
as a significant predictor of the treatment outcome in children affected by acute lym-
phoblastic leukemia, although these findings have not been confirmed in adults.
33
-
35
Another study showed an increased response to preoperative chemotherapy in breast
cancer patients homozygous for the C3435T genotype,
36
whereas conflicting results
have been reported regarding the impact of genetic variation of the MDR1 gene
(in particular, G2677T/A) on the response to paclitaxel chemotherapy in patients
with ovarian carcinoma.
37
Taken together, all these findings suggest that despite the
numerous conflicting results, an interethnic difference in ABCB1 SNPs exists, and
several ABCB genetic variants, resulting in altered Pgp function, may contribute to
the interindividual variability in toxicity and pharmacokinetics of drugs and to the
susceptibility to certain diseases. Additional studies to clarify the clinical implications
of ABCB1 polymorphisms are needed.
13
,
38
Main Substrate Classes (Clinically Applied)
Pgp presents high transport capacity
and broad substrate specificity. A wide number of clinically relevant drugs with struc-
turally different features belonging to different classes [e.g., several anticancer drugs,
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