Received for publication September 19, 2007.
Revised December 17, 2007.
Accepted for publication January 2, 2008.

Establishment of a set of double transfectants co-expressing organic anion transporting polypeptide 1B3 (OATP1B3) and hepatic efflux transporters for the characterization of the hepatobiliary transport of telmisartan acylglucuronide

Abstract

In the hepatic uptake of organic anions, organic anion transporting polypeptide (OATP)1B1 is believed to be mainly involved. We have constructed a set of double transfected cells co-expressing OATP1B1 and hepatic efflux transporter and characterized the transcellular transport of several anions. Recent reports have also suggested the importance of OATP1B3 in the hepatic uptake of some compounds. However, there is little information about OATP1B3-selective substrate and no good tool for the evaluation of efflux transporters of OATP1B3 substrates. In the present study, we found an OATP1B3-selective substrate and established a novel set of double transfectants expressing OATP1B3. Telmisartan acylglucuronide (tel-glu) is a main metabolite of telmisartan, an angiotensin II receptor antagonist. Tel-glu is recognized by hepatobiliary transport systems and efficiently distributed to liver. Several studies using rat and human hepatocytes and transporter-expressing cells revealed that OATP1B3 was responsible for the hepatic uptake of tel-glu in humans. By utilizing double transfectants expressing OATP1B3, we investigated the transcellular transport of tel-glu as well as estradiol 17-D-glucuronide (E₂17G) and cholecystokinin octapeptide (CCK-8) to identify the responsible efflux transporters in their biliary excretion. Vectorial basal-to-apical transport of tel-glu was observed in all kinds of double transfectants expressing OATP1B3. In contrast, basal-to-apical transport of E₂17G and CCK-8 was seen only in OATP1B3/MRP2 double transfectant compared with OATP1B3-expressing cells. Therefore, the newly established set of double transfectants expressing OATP1B3 combined with OATP1B1-expressing double transfectants can be used as a powerful tool for the rapid identification of hepatic uptake and efflux transporters of organic anions.

Key words: ABC transporters, drug distribution, drug efflux, hepatic elimination, hepatic uptake, hepatobiliary transport, organic anion transport, transporters

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