OATP1B1 and OATP1B3 are major hepatic drug transporters whilst OATP1A2 is mainly located in the brain but is also located in liver and several other organs. These transporters affect the distribution and clearance of many endo- and xenobiotics and have been reported to have functional SNPs. We have assessed the substrate specificites of these transporters for a panel of antiretrovirals and investigated the effects of SNPs within these transporters on the pharmacokinetics of lopinavir. SLCO1A2, SLCO1B1 and SLCO1B3 were cloned, verified and used to generate cRNA for use in the Xenopus laevis oocyte transport system. Using the oocyte system, antiretrovirals were tested for their substrate specificities. Plasma samples (n=349) from the Liverpool therapeutic drug monitoring registry were genotyped for SNPs in SLCO1A2, SLCO1B1 and SLCO1B3 and associations between SNPs and lopinavir plasma concentrations were analysed. Antiretroviral protease inhibitors, but not non-nucleoside reverse transcriptase inhibitors are substrates for OATP1A2, OATP1B1 and OATP1B3. Furthermore, ritonavir was not an inhibitor of OATP1B1. The 521T>C polymorphism in SLCO1B1 was significantly associated with higher lopinavir plasma concentrations. No associations were observed with functional variants of SLCO1A2 and SLCO1B3. These data add to our understanding of the factors that contribute to variability in plasma concentrations of protease inhibitors. Further studies are now required to confirm the association of SLCO1B1 521T>C with lopinavir plasma concentrations and to assess the influence of other polymorphisms in the SLCO family.

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. MethodsSLCO1A2 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. Summary of results SLCO1A2-injected oocytes had significantly higher E3Saccumulation 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 5,432), 5,945) and 3,899 (2,815) ng/mL, respectively (p > 0.05). Also, no association with peak concentrations was observed. ConclusionThese 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.

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demonstrated an excellent treatment response. However, as MRD does not account for extramedullary disease, her treatment was adapted to include an additional intensive block.Leukaemic infi ltration of the skin or leukaemia cutis (LC) can present in myeloid or lymphoid leukaemia. 1 LC is a rare presenting feature in 1.2% of childhood ALL cases. 2 Lesions can be solitary or multiple, non-pruritic, erythematous, violaceous papules or nodules frequently involving the face, trunk and limbs. 3 4 LC can occasionally precede blood or marrow involvement by several months; this phase is referred to as aleukaemia cutis. 5 LC can occur in both standard and highrisk ALL groups, 3 5 but the prognostic signifi cance in childhood ALL remains to be determined. 2