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Session 111
Poster Abstracts Pharmacology of NRTIs Wednesday, 1:30 - 3:30 pm Hall A |
Background: The ATP-binding cassette transporters may
significantly impact the pharmacologic behavior of substrate drugs. Of these
transporters, MRP4 and BCRP influence the intracellular concentrations and
pharmacologic activity of zidovudine (ZDV)- and lamivudine (3TC)-phosphates
in vitro and MRP2 may influence indinavir (IDV) concentrations in mice. Our objective was
to investigate associations between single nucleotide polymorphisms (SNP) in
these genes with intracellular ZDV- and 3TC-triphosphate concentrations and IDV
oral clearance (CL/F) in HIV-infected patients.
Methods: Subjects were antiretroviral-naïve and
participating in an 18-month study of ZDV, 3TC, and IDV. IDV CL/F was averaged
from 3 intensive pharmacokinetic studies per patient. Median ZDV- and
3TC-triphosphate concentrations were determined from 12 planned collections per
patient. Genotypes were determined for 8 SNP by
direct sequencing or pyro-sequencing analyses. For
each SNP, log-transformed pharmacologic data were compared between homozygous
wild-type and variant carriers using regression.
Results: We evaluated 33 subjects: 7 were black, 23 white, 2 Hispanic, and 1
Pacific-Islander (black versus non-black for analyses). The table lists the SNP,
frequencies, and p values for multivariable
regression. Blank cells denote p >
0.07. IDV CL/F was controlled for previously determined CYP3A5 expressor status (n=11 expressors;
7 of 7 blacks) and ZDV- and 3TC-triphosphates were controlled for sex (n = 4
women; 3 of 7 blacks). ZDV-triphosphate was approximately 1.9-fold higher for MRP4 G3724A
variant carriers, whereas 3TC-triphosphate was approximately 1.2-fold higher
for T4131G variant carriers (consistent between the sexes). In CYP3A5 expressors, IDV CL/F was 1.4-fold faster in MRP2 C-24T variant
carriers versus wild-type.
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Gene |
SNP |
Variant Allele |
IDV CL/F |
ZDV-TP |
3TC-TP |
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Frequency (%) |
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MRP4 |
C1612T |
T = 7.8* |
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MRP4 |
G3463A |
A = 15.6 |
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MRP4 |
G3724A |
A = 4.5* |
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p = 0.06 |
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MRP4 |
T4131G |
G = 37.9 |
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p = 0.004 |
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MRP2 |
C-24T |
T = 21.2 |
p = 0.06 |
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MRP2 |
G1249A |
A = 19.6 |
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BCRP |
G34A |
A = 9.1* |
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BCRP |
C421A |
A = 7.6 |
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* = more common
in blacks
Conclusions: The intracellular triphosphate
concentrations of ZDV and 3TC were
associated with polymorphisms in the MRP4 gene. IDV CL/F was associated with a
polymorphism in the MRP2 promoter. These new findings in patients suggest that
genetic variability in human drug transporters may account for variability in
the clinical pharmacologic behavior of antiretroviral drugs.
Keywords: clinical pharmacology; pharmacogenetics; pharmacokinetics
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