BACKGROUND:
MDR1 encodes P-glycoprotein, an efflux transporter that protects sensitive
tissues including brain, immune cells, and fetuses against substrate
xenobiotic exposures. P-gp forms a gut barrier against substrate absorption
and clears substrates from blood into urine, bile, and intestine. HIV
protease inhibitors are P-gp substrates in vitro and in animals. Our
objective was to characterize the association of MDR1 C3435T and G2677T
genotypes with IDV disposition and antiviral dynamics.
METHODS:
Antiretroviral naïve adults were participating in a 52-week study of
zidovudine, lamivudine, and IDV. Intensive plasma sampling for IDV was
conducted at week 2; concentrations were measured with HPLC/UV.
Pharmacokinetics were estimated standard modeling and data inspection.
Plasma HIV-RNA was collected monthly; PBMC pellets were stored. All data
and PBMC pellets were de-identified and re-coded. Following institutional
review board approval, MDR1 genotypes were obtained by PCR-direct sequencing
with PolyPhred analysis. Parametric statistics were used for comparisons.
RESULTS:
33 subjects were genotyped. For the 2677G>T, (Ala893Ser) and 3435C>T
respectively, 8 subjects were GG/CC; 4 GG/CT; 16 GT/CT; 1 GT/TT; 1 TT/CT;
and 3 TT/TT; indicating significant linkage disequilibrium between the
polymorphic sites. IDV CL/F (L/H/kg) was lower in the 2677 TT compared with
GG groups, 0.48 versus 0.82, respectively (P=0.02), and also in the 3435 TT
compared with CC groups, 0.49 versus 0.84, respectively (P=0.04). IDV Cmax
(µg/mL) was higher in the 2677 TT versus GG group, 10.0 versus 7.2,
respectively (P=0.06), and when normalized for dose, 0.93 versus 0.62 per
mg/kg/dose (P=0.04). Cmax was not significantly related with C3435T. 2677 TT
subjects had a larger decline in log HIV-RNA at week 52 or study exit
compared with GT or GG groups, -3.7 versus -3.2 and -2.2 (P=0.008 and 0.04),
respectively. Baseline HIV-RNA was marginally higher in the 3435 TT versus
CC groups, 5.1 versus 4.4 log copies/mL (P=0.06), but not among 2677
genotypes.
CONCLUSION:
These findings indicate that MDR1 genotypes influence IDV pharmacokinetics
and antiviral dynamics. Other studies have reported conflicting data between
MDR1 genotypes and substrate disposition and effects. In this study, MDR1
2677TT (Ser893) was associated with both higher IDV plasma concentrations
and stronger antiviral responses.
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