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Background: Pravastatin (PVA) is subject to pre-systemic conversion to an inactive isomer, 3’α-iso-pravastatin acid (3αPVA), in the acidic environment of the stomach. Inter-individual differences in the relative amounts of circulating PVA and 3α-PVA have been observed in adults and confirmed in children. Our previous investigation in children suggested that 3αPVA was a substrate of OATP1B1, but additionally a possible competitive inhibitor of OATP1B1.As a consequence, PVA concentrations at the site of drug action in the liver may be reduced further, potentially compromising efficacy.

In the present study, we examined the functional consequences of 3α-PVA on OATP1B1-mediated PVA transport and whether it is a competitive inhibitor of OATP1B1.

Methods: Site directed mutagenesis was performed to generate SLCO1B1 genotypes of interest (*1a, *1b, *5, *15). Human embryonic kidney (HEK293) cells were grown and plated at 200 000 cells per well in 24-well plates. Twenty-four hours later the cells were transfected with the aforementioned plasmids. Forty-eight hours later cell-based transport was performed with radiolabelled [3H]-pravastatin sodium salt. Non-radioactive pravastatin sodium salt and 3’α-iso-pravastatin sodium salt was used for PVA transport and 3αPVA studies, respectively. Data were analyzed for significant differences amongst genotype groups using ANOVA followed by Tukey’s multiple comparisons test. IC50 and kinetic parameters were calculated using non-linear regression analysis.

Results: Pravastatin transport in SLCO1B1 variants (*5,*15) was significantly decreased compared to the reference genotype *1a and *1b (Km [µM]: *1a 18.2±0.9; *1b 17.9±3.3; *5 34.2± 9.7; *15 34.1±6.1; p≤0.05; Vmax [pmol/mg/min]: *1a 104.9±13.1; *1b 93.7±16.7; *5 44.8±15.9; *15 62.3±22.5; p≤0.05). *1a and *1b were not significantly different with respect to pravastatin transport. Intrinsic clearance was diminished nearly 4 to 5-fold in SLCO1B1 variants compared to reference genotypes (Vmax/Km [µl/min/mg]: *1a 5.8 ± 0.8; *1b 5.7 ± 1.9; *5 1.3 ± 0.2; *15 1.8 ± 0.3; p≤0.01).

Pravastatin transport was inhibited by 3αPVA for all genotypes. However, there was more pronounced inhibition in the SLCO1B1 variant genotypes compared to reference genotypes (IC50 [µM]: *1a 15.9±1.9; *1b 18.6±5.7; *5 3.9±2.0; *15 4.4±0.8; p≤0.01).

Discussion: The functional consequences of 3αPVA formation on PVA transport was confirmed in our study. Mechanistically, we confirmed our observation in humans that 3αPVA inhibits OATP1B1 transport. However, this effect is more pronounced in variant genotypes as shown by lower IC50 values compared to the reference genotypes. This highlights another source of variation that must be taken into consideration when trying to optimize the pravastatin dose-exposure relationship in humans.

Document Type


Functional Consequences of Pravastatin Isomerization on OATP1B1-Mediated Transport



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