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Drug Metabolism and Disposition Fast Forward
First published on July 27, 2004; DOI: 10.1124/dmd.104.000497

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Received for publication May 3, 2004.
Revised July 22, 2004.
Accepted for publication July 22, 2004.

Hepatic transport of PKI166 - an epidermal growth factor receptor kinase inhibitor of the pyrrolo-pyrimidine class - and its main metabolite ACU154

Tappei Takada 1, Markus Weiss 2*, Olivier Kretz 2, Gerhard Gross 2, Yuichi Sugiyama 1

1 The University of Tokyo 2 Novartis Pharma AG, Preclinical Safety

* Address correspondence to: E-mail: markus.weiss{at}pharma.novartis.com

Abstract

PKI166, a specific inhibitor of the tyrosine kinase activity of two epidermal growth factor receptors, was under development for the treatment of cancer. In preclinical studies PKI166 was mainly cleared by metabolism and its metabolites were eliminated by biliary excretion, emphasizing the role of liver transport processes for its disposition. Here the transport properties of [14C]PKI166 and its main metabolite [14C]ACU154 - an O-glucuronide - were analysed using (I) MDCKII cells stably transfected with human MRP2 and/or OATP2 and (II) liver canalicular membrane vesicles (CMVs) prepared from Wistar and mrp2 deficient TR- rats. Analysis of transport through MDCKII cells revealed that [14C]ACU154 was a substrate of MRP2 and OATP2. Rat mrp2 was shown to transport [14C]ACU154 with a Km of approximately 1 µM. [14C]PKI166 efficiently crossed MDCKII cells particularly towards the apical side, but expression of MRP2 and/or OATP2 did not increase the flux. The effect of PKI166 and ACU154 on transport of [3H]estradiol-17{beta}-D-glucuronide (EG, via mrp2/MRP2 and OATP2) or [3H]taurocholic acid (TCA, via bsep) was analyzed. PKI166 inhibited the transport of [3H]EG by OATP2. ACU154 did strongly inhibit [3H]TCA uptake into CMVs from Wistar but not from TR- rats, demonstrating a dependency of bsep inhibition on mrp2 activity. ATP dependent uptake of [3H]EG into CMVs from Wistar rats was inhibited by ACU154 but up to four fold increased by PKI166. In conclusion OATP2 and MRP2/mrp2 were identified as transporters involved in ACU154 transport into bile. Both PKI166 and its O-glucuronide ACU154 affected mrp2/MRP2, OATP2 and/or bsep mediated transport processes.


Key words: anticancer agents, biliary excretion, drug transport, hepatobiliary transport


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