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

Abstract

We developed a pravastatin derivative, sodium (3R,5R)-3,5-dihydroxy-7-((1S,2S,6S,8S)-6-hydroxy-2-methyl-8-((1-[ 11 C]-(E)-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8a-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 6 4.8 and 24.6 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 , 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CL int,bile ) of [ 11 C]DPV, which was 12.2 6 1.5 ml/min per kilogram in the control rat, decreased by 60% and 89% in rifampicin-treated rat and EHBR (P , 0.05), respectively. These results indicate that [

Utility of Bilirubins and Bile Acids as Endogenous Biomarkers for the Inhibition of Hepatic Transporters

“…In this study, [ 3 H]E 2 17bG was used as a typical substrate of rOatps for the inhibition study because radiolabeled bilirubin glucuronide could not be commercially obtained. When pravastatin was used as a substrate for rOatps, the uptake was decreased to 50% by 1 mM rifampicin in a rat hepatocytes study (Shingaki et al, 2013). The discrepancy in the inhibitory effects between the reported results and our results may be due to the differences in the contribution of Oatp molecules to the rat hepatic uptake of E 2 17bG and pravastatin.…”

A Clinical Quantitative Evaluation of Hepatobiliary Transport of [11C]Dehydropravastatin in Humans Using Positron Emission Tomography

“…We developed a new PET probe, sodium (3R, 5R)-3, 5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8-((1-[ ]DPV (544 6 204 and 10.2 6 3.5 ml/min per gram liver, respectively) in humans were lower than the previously reported corresponding parameters in rats (1800 and 298 ml/min per gram liver, respectively) (Shingaki et al, 2013). Furthermore, rifampicin treatment significantly reduced CL uptake, liver and CL int, bile by 58% and 44%, respectively.…”

“…We have established several PET probes for assessing drug transporters and demonstrated their usefulness in pharmacokinetic and DDI studies in animals (Takashima et al, 2010(Takashima et al, , 2011Shingaki et al, 2013) and humans . However, the functional characterization of multispecific drug transporters and the DDIs in vivo have not been fully analyzed to ensure the accuracy of pharmacokinetic prediction.…”

Organic Anion Transporting Polypeptide (OATP)1B1 and OATP1B3 as Important Regulators of the Pharmacokinetics of Substrate Drugs

“…Recently, to non-invasively perform the real-time measurement of the tissue concentration of drugs, several kinds of positron emission tomography (PET) probes for evaluating OATP function have been created and characterized in rodents and humans. [70][71][72][73] By using the time profile data for tissue concentration as well as the plasma concentration of drugs to optimize the model parameters, we can further increase the reliability of a PBPK model. Another strategy is to create methods for extracting multiple candidate sets of model parameters which can reproduce a limited number of clinical data.…”