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- Open Access
Lopinavir is a substrate for SLCO1A2 but 516A>C and 38T>C polymorphisms do not influence lopinavir plasma concentrations
© Shallcross et al; licensee BioMed Central Ltd. 2008
- Published: 10 November 2008
- Therapeutic Drug Monitoring
- Intersubject Variability
- Kozak Sequence
The SLCO1A2 influx transporter is located in the liver, intestine, brain and kidneys. A number of functional single nucleotide polymorphisms (SNPs) have been reported in the SLCO1A2 gene (including 516A>C and 38 T>C). The aim of this study was to determine if LPV is a substrate for SLCO1A2 in vitro and to assess whether these SNPs impact upon LPV plasma concentrations.
SLCO1A2 was cloned (with Kozak sequence) into pBluescriptII-KSM, flanked by the 5' and 3' X. laevis β-globin UTR and cRNA was generated by in vitro transcription. SLCO1A2 or water-injected oocytes were incubated with estrone-3-sulphate ([3H]-E3S; 1 μM; 0.33 μCi/ml; positive control) or [3H]-LPV (1 μM, 0.33 μCi/ml). Statistical analyses were performed on log transformed data by a paired t-test (n = 4 experiments with at least six replicates). Archived plasma samples were available from patients (n = 400) who had previously undergone therapeutic drug monitoring (TDM). LPV peak (2–6 hr) and trough (10–14 hr) concentrations were available. The following exclusion criteria were applied; age <18 years, pregnancy, deranged LFTs and the use of rifamycins, anticonvulsants, acid-reducing agents or NNRTIs. SLCO1A2 516A>C and 38T>C were genotyped using real-time allelic discrimination and statistical analysis was performed by Mann Whitney.
SLCO1A2-injected oocytes had significantly higher E3S accumulation compared to water-injected oocytes (0.51 ± 0.17 vs. 0.16 ± 0.04 (pmol/oocyte), p < 0.05) and significantly higher accumulation of LPV (4.30 ± 0.72 vs. 2.14 ± 0.43, p < 0.05). The allele frequencies of 516C and 38C were 2.5% and 5.8%, respectively. The median (range) Ctrough for 516 AA, AC and CC were 5,170 (818–22,432) 4,859 (2,008–14,273) and 5,609 (1,174–8,396) ng/mL, respectively (p > 0.05). The median (range) Ctrough for 38 TT, TC and CC were 5,023 (818–22,432), 5,778 (833–21,945) and 3,899 (2,380–6,815) ng/mL, respectively (p > 0.05). Also, no association with peak concentrations was observed.
These data indicate that LPV is a substrate for SLCO1A2. However, SLCO1A2 516A>C and 38T>C did not influence plasma concentrations of LPV and does not therefore appear to be a major determinant of intersubject variability. These data must be interpreted with caution due to the limitations associated with a TDM cohort (i.e. selection bias and lack of ethnicity data). As with all pharmacogenetic data, the findings warrant confirmation in other cohorts.
This article is published under license to BioMed Central Ltd.