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First published on April 17, 2008; DOI: 10.1124/dmd.107.019398

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Received for publication October 24, 2007.
Revised April 14, 2008.
Accepted for publication April 16, 2008.

Cellular accumulation of cholyl-glycylamido-fluorescein in sandwich-cultured rat hepatocytes: kinetic characterization, transport mechanisms and effect of HIV protease inhibitors

Zhi-wei Ye 1, Patrick Augustijns 1, Pieter Annaert 1*

1 Katholieke Universiteit Leuven (KULeuven)

* Address correspondence to: E-mail: pieter.annaert{at}pharm.kuleuven.be

Abstract

The present study was aimed at characterizing the in vitro cellular uptake mechanism and kinetics of the bile salt analogue cholyl-glycylamido-fluorescein (CGamF) in sandwich-cultured rat hepatocytes (SCRH). Concentration-dependent inhibition of active CGamF accumulation by seven HIV protease inhibitors (PI) was also determined and compared to inhibition data obtained with taurocholate (TC) as a substrate. A Km value of 9.3 ± 2.6 µM was obtained for saturable CGamF accumulation in SCRH. The Oatp inhibitor rifampicin (100 µM) inhibited CGamF (1 µM) accumulation in SCRH by 72 %; sodium depletion did not further reduce CGamF accumulation. In contrast, TC accumulation was reduced by only 25% in the presence of rifampicin, while additional sodium depletion resulted in a complete loss of TC accumulation. These data imply that Oatp(s) and Ntcp preferentially mediate hepatic uptake of CGamF and TC, respectively. Co-incubation of CGamF with HIV PI (amprenavir, atazanavir, darunavir, indinavir, nelfinavir, ritonavir, saquinavir), revealed that five of them had a concentration-dependent inhibitory effect on CGamF accumulation in SCRH, with IC50 values between 0.25 ± 0.07 and 43 ± 12 µM. The rank order for inhibition of CGamF accumulation in SCRH was: ritonavir >> saquinavir > atazanavir > darunavir > amprenavir. Indinavir (up to 100 µM) did not alter CGamF accumulation, while nelfinavir solubility was limited to 10 µM. Taken together, these findings illustrate the utility of CGamF as a suitable probe (complementary to TC) for rapid in vitro determination of interaction potential with sodium-independent uptake mechanisms (likely Oatps) in rat liver.


Key words: active transport, antivirals, bile acid transport, cellular transport, drug interactions, hepatic transport, hepatic uptake, hepatocytes


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