PT - JOURNAL ARTICLE AU - Oscar Briz AU - Maria Angeles Serrano AU - Noemi Rebollo AU - Bruno Hagenbuch AU - Peter J. Meier AU - Hermann Koepsell AU - Jose J.G. Marin TI - Carriers Involved in Targeting the Cytostatic Bile Acid-Cisplatin Derivatives<em>cis</em>-Diammine-chloro-cholylglycinate-platinum(II) and<em>cis</em>-Diammine-bisursodeoxycholate-platinum(II) toward Liver Cells AID - 10.1124/mol.61.4.853 DP - 2002 Apr 01 TA - Molecular Pharmacology PG - 853--860 VI - 61 IP - 4 4099 - http://molpharm.aspetjournals.org/content/61/4/853.short 4100 - http://molpharm.aspetjournals.org/content/61/4/853.full SO - Mol Pharmacol2002 Apr 01; 61 AB - Molecular bases for targeting bile acid-cisplatin derivatives Bamet-R2 [cis-diammine-chloro-cholylglycinate-platinum(II)] and Bamet-UD2 [cis-diammine-bisursodeoxycholate-platinum(II)] toward liver cells were investigated. Carriers for bile acids [human Na+-taurocholate cotransporting polypeptide (NTCP)], organic anions [organic anion transporting polypeptide (OATP)], and organic cations [organic cation transporter (OCT)] were expressed inXenopus laevis oocytes (XO) and Chinese hamster ovary (CHO) cells. Drug uptake was measured by flameless atomic absorption of platinum. Rat Oatp1- or rat Ntcp-transfected CHO cells were able to take up Bamets, but not cisplatin, severalfold more efficiently than wild-type cells. This uptake was enhanced by butyrate-induced expression of both carriers. Uptake of both Bamets by Ntcp-transfected CHO cells was stimulated by extracellular sodium. The amount of Bamets, but not cisplatin, taken up by XO was enhanced when expressing OATP-A, OATP-C, NTCP, OCT1, or OCT2, a nonhepatic OCT isoform used for comparative purposes. Bamet uptake by XO was inhibited by known substrates of these carriers (glycocholate for NTCP and OATP-C, ouabain for OATP-A, and quinine for OCT1 and OCT2). Drug uptake versus substrate concentration revealed saturation kinetics (K m was in the 8–58 μM range), with the following order of efficiency of transport (V max/K m) for Bamet-R2: OATP-C &gt; OCT2 &gt; OATP-A &gt; NTCP &gt; OCT1; and the following order of efficiency of transport for Bamet-UD2: OATP-C &gt; OCT2 &gt; OATP-A &gt; OCT1 &gt; NTCP. Increasing the generation of cationic forms of Bamets by incubation in the absence of chloride increased drug uptake by OATP-A, OCT1, and OCT2 but reduced that achieved by NTCP and OATP-C. These results suggest a role for carriers of organic anions and cations in Bamet-R2 and Bamet-UD2 uptake, which may determine their ability to accumulate in liver tumor cells and/or be taken up and efficiently excreted by hepatocytes.