Abstract:
UNLABELLED:Better prediction of drug disposition prior to the clinical trial is critical for the efficient development of new drugs. The purpose of this study is to develop a novel multiple assessment methodology of hepatocellular drug disposition from drug uptake to efflux including biliary and basolateral excretion, in a single packaged procedure. We started a sandwich culture using rat primary hepatocytes. After five days culture, the hepatocytes were incubated with a dosing solution including CDF or Rhodamine 123. Three distinct sequences were then performed in parallel: disrupting and maintaining the tight junctions comprising a bile canalicular network at 37 °C, and maintaining the network at 4 °C. Supernatant fractions were collected from each sequence, and followed by the cell lysate collection. The disposition rates of basolateral efflux by diffusion, by transporter-mediation, biliary excretion, and residual cellular fraction of CDF and Rhodamine 123 were 38.2% and 11.0%, 26.6% and 12.1%, 18.6% and 4.9%, and, 16.7% and 72.0%, respectively. CDF was likely to excrete extracellularly whereas Rhodamine 123 tended to remain intracellularly. CDF showed a relatively higher biliary excretion rate than Rhodamine 123. This novel protocol may contribute to improve the predictability of pharmacokinetics eventually in human, and streamline new drug development. CHEMICAL COMPOUNDS:5(6)-Carboxy-2',7'-dichlorofluoroscein (PubChem CID: 132525); Rhodamine 123 (PubChem CID: 65217).
journal_name
Drug Metab Pharmacokinetjournal_title
Drug metabolism and pharmacokineticsauthors
Takahashi R,Ichikawa H,Kanda Kdoi
10.1016/j.dmpk.2015.12.001subject
Has Abstractpub_date
2016-04-01 00:00:00pages
167-71issue
2eissn
1347-4367issn
1880-0920pii
S1347-4367(15)00080-4journal_volume
31pub_type
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