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Evaluation of Oatp and Mrp2 activities in hepatobiliary excretion using newly developed positron emission tomography tracer [11C]dehydropravastatin in rats.
Shingaki, Tomotaka; Takashima, Tadayuki; Ijuin, Ryosuke; Zhang, Xuan; Onoue, Tomohiro; Katayama, Yumiko; Okauchi, Takashi; Hayashinaka, Emi; Cui, Yilong; Wada, Yasuhiro; Suzuki, Masaaki; Maeda, Kazuya; Kusuhara, Hiroyuki; Sugiyama, Yuichi; Watanabe, Yasuyoshi.
Afiliação
  • Shingaki T; RIKEN Center for Life Science Technologies (T.S., Y.K., T.Ok., E.H., Y.C., Y.Wad., Y.Wat.) and RIKEN Center for Molecular Imaging Sciences, Kobe, Hyogo, Japan (T.S., T.T., R.I., T.Ok., Y.K., E.H., Y.C., Y.Wad., M.S., Y.Wat.); Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan (X.Z., T.On., K.M., H.K.); and Sugiyama Laboratory, RIKEN Innovation Center, Yokohama Bio Industry Center, Yokohama, Kanagawa, Japan (Y.S.).
J Pharmacol Exp Ther ; 347(1): 193-202, 2013 Oct.
Article em En | MEDLINE | ID: mdl-23926287
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 (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 [(11)C]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 [(11)C]DPV by 30% (P < 0.05), whereas these parameters were unchanged in EHBR. Meanwhile, the canalicular efflux clearance (CLint,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 < 0.05), respectively. These results indicate that [(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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sistema Biliar / Pravastatina / Transportadores de Cassetes de Ligação de ATP / Hepatócitos / Transportadores de Ânions Orgânicos / Tomografia por Emissão de Pósitrons Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Sistema Biliar / Pravastatina / Transportadores de Cassetes de Ligação de ATP / Hepatócitos / Transportadores de Ânions Orgânicos / Tomografia por Emissão de Pósitrons Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2013 Tipo de documento: Article