期刊
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
卷 347, 期 1, 页码 193-202出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/jpet.113.206425
关键词
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资金
- Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT)
- Japan Society for the Promotion of Science (JSPS) KAKENHI [24229002]
- Grants-in-Aid for Scientific Research [24659574, 23136101, 25460147, 25242070] Funding Source: KAKEN
We developed a pravastatin derivative, sodium (3R, 5R)-3,5-dihydroxy-7-((1S, 2S, 6S, 8S)-6-hydroxy-2-methyl-8-((1-[C-11]-(E)-2-methyl-but-2-enoyl)oxy)-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)heptanoate ([C-11]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. [C-11]DPV underwent biotransformation to produce at least two metabolites in rat, but metabolism of [C-11]DPV occurred negligibly in human hepatocytes during a 90-minute incubation. After intravenous injection, [C-11]DPV was mainly distributed to the liver and kidneys, where the tissue uptake clearances (CLuptake,liver and CLuptake, kidney) were blood-flow-limited (73.6 +/- 4.8 and 24.6 +/- 0.6 ml/min per kilogram, respectively). Systemic elimination of [C-11]DPV was delayed in rifampicin-treated rat and an Mrp2-deficient mutant rat, Eisai hyperbilirubinemic mutant rat (EHBR). Rifampicin treatment decreased both CLuptake,liver and CLuptake,kidney of [C-11]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,bile) of [C-11]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 < 0.05), respectively. These results indicate that [C-11]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 [C-11]DPV. PET using [C-11]DPV is feasible for studies prior to the future clinical investigation of OATP and MRP2 functionality, especially for personalized medicine.
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