A clinical quantitative evaluation of hepatobiliary transport of [11C]Dehydropravastatin in humans using positron emission tomography

Various positron emission tomography (PET) probes have been developed to assess the in vivo activities of drug transporters in humans, that aid in the prediction of pharmacokinetic properties of drugs and the impact of drug-drug interactions. We developed a new PET probe, [ 11C ]dehydropravastatin ([ 11 C]DPV), and demonstrated its usefulness for the quantitative investigation of Oatps/SLCO and Mrp2/ABCC2 in rats. To further analyze the species differences and verify the pharmacokinetic parameters in humans, serial PET scanning of the abdominal region with [ 11 C]DPV was performed in six healthy volunteers with and without an OATP1Bs and MRP2 inhibitor, rifampicin (600 mg, oral), in a crossover fashion. After intravenous injection, [ 11 C]DPV rapidly distributed to the liver and kidney followed by secretion into the bile and urine. Rifampicin significantly reduced the liver distribution of [ 11 C]DPV 3.0-fold, resulting in a 7.5-fold reduced amount of excretion into the bile and the delayed elimination of [ 11 C]DPV from the blood circulation. The hepatic uptake clearance (CL uptake, liver ) and canalicular efflux clearance (CL int, bile ) of [ 11 C]DPV (11.4 ± 4.0 mL/min/kg, and 10.2 ± 3.5 μL/min/g liver, respectively) in humans were lower than the corresponding parameters in rats. Furthermore, rifampicin treatment significantly reduced the CL uptake, liver and CL int, bile by 58 and 44%, respectively. These results suggest that PET imaging with [ 11 C]DPV is an effective tool for quantitatively characterizing the OATP1Bs and MRP2 functions in the human hepatobiliary transport system.