Evaluation of Oatp and Mrp2 Activities in Hepatobiliary Excretion Using Newly Developed Positron Emission Tomography Tracer [11C]Dehydropravastatin in Rats

We developed a pravastatin derivative, sodium (3 R ,5 R )-3,5-dihydroxy-7-((1 S ,2 S ,6 S ,8 S )-6-hydroxy-2-methyl-8-((1-[ 11 C]-( E )-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8 a -hexahydronaphthalen-1-yl)heptanoate ([ 11 C]DPV), as a positron emission tomography (PET) probe for noninvasive measurement of hepatobiliary transport, and conducted pharmacokinetic analysis in rats as a feasibility study for future clinical study. Transport activities of DPV in freshly isolated rat hepatocytes and rodent multidrug resistance–associated protein 2 (rMrp2; human, MRP2)-expressing membrane vesicles were similar to those of pravastatin. Rifampicin diminished the uptake of DPV and pravastatin by the hepatocytes, with similar inhibition potency. [ 11 C]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [ 11 C]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [ 11 C]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CL uptake,liver and CL uptake,kidney ) were blood-flow–limited (73.6 ± 4.8 and 24.6 ± 0.6 ml/min per kilogram, respectively). Systemic elimination of [ 11 C]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CL uptake,liver and CL uptake,kidney of [ 11 C]DPV by 30% ( P int,bile ) of [ 11 C]DPV, which was 12.2 ± 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR ( P 11 C]DPV is taken up into the liver by organic anion-transporting polypeptides (rodent, Oatps; human, OATP) and excreted into bile by Mrp2 in rat, and that rifampicin may inhibit Mrp2 as well as Oatps, and consequently increase systemic exposure of [ 11 C]DPV. PET using [ 11 C]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine.