Carriers involved in targeting the cytostatic bile acid-cisplatin derivatives cis-diammine-chloro-cholylglycinate-platinum(II) and cis-diammine-bisursodeoxycholate-platinum(II) toward liver cells.
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 in Xenopus 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 microM range), with the following order of efficiency of transport (V(max)/K(m)) for Bamet-R2: OATP-C > OCT2 > OATP-A > NTCP > OCT1; and the following order of efficiency of transport for Bamet-UD2: OATP-C > OCT2 > OATP-A > OCT1 > 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.
Briz
Oscar
O
Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain.
Serrano
Maria Angeles
MA
Rebollo
Noemi
N
Hagenbuch
Bruno
B
Meier
Peter J
PJ
Koepsell
Hermann
H
Marin
Jose J G
JJ
D000818:Animals; D000838:Anions / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001647:Bile Acids and Salts / Q000378:metabolism*; D016466:CHO Cells; D002412:Cations / Q000378:metabolism; D006224:Cricetinae; D004337:Drug Carriers / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D009865:Oocytes / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D014982:Xenopus laevis
D000838:Anions; D000970:Antineoplastic Agents; C416424:Bamet-UD2; D001647:Bile Acids and Salts; D002412:Cations; D004337:Drug Carriers; D009944:Organoplatinum Compounds; C408382:diamminebis(ursodeoxycholate(O,O'))platinum(II); D014580:Ursodeoxycholic Acid