Evaluation of (99m)technetium-mebrofenin and (99m)technetium-sestamibi as specific probes for hepatic transport protein function in rat and human hepatocytes.
Pharm Res
; 27(9): 1987-98, 2010 Sep.
Article
em En
| MEDLINE
| ID: mdl-20652625
ABSTRACT
PURPOSE:
This study characterized 99mTc-Mebrofenin (MEB) and 99mTc-Sestamibi (MIBI) hepatic transport and preferential efflux routes (canalicular vs. basolateral) in rat and human sandwich-cultured hepatocytes (SCH).METHODS:
99mTc-MEB and 99mTc-MIBI disposition was determined in suspended hepatocytes and in SCH in the presence and absence of inhibitors and genetic knockdown of breast cancer resistance protein (Bcrp).RESULTS:
The general organic anion transporting polypeptide (Oatp/OATP) inhibitor rifamycin SV reduced initial 99mTc-MEB uptake in rat and human suspended hepatocytes. Initial 99mTc-MIBI uptake in suspended rat hepatocytes was not Na+-dependent or influenced by inhibitors. Multidrug resistance-associated protein (Mrp2/MRP2) inhibitors decreased 99mTc-MEB canalicular efflux in rat and human SCH. 99mTc-MEB efflux in human SCH was predominantly canalicular (45.8 +/- 8.6%) and approximately 3-fold greater than in rat SCH. 99mTc-MIBI canalicular efflux was similar in human and rat SCH; basolateral efflux was 37% greater in human than rat SCH. 99mTc-MIBI cellular accumulation, biliary excretion index and in vitro biliary clearance in rat SCH were unaffected by Bcrp knockdown.CONCLUSION:
99mTc-MEB hepatic uptake is predominantly Oatp-mediated with biliary excretion by Mrp2. 99mTc-MIBI appears to passively diffuse into hepatocytes; biliary excretion is mediated by P-gp. The SCH model is useful to investigate factors that may alter the route and/or extent of hepatic basolateral and canalicular efflux of substrates.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
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Compostos de Organotecnécio
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Tecnécio Tc 99m Sestamibi
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Hepatócitos
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Iminoácidos
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Fígado
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Pharm Res
Ano de publicação:
2010
Tipo de documento:
Article