Transport and biotransformation of the new cytostatic complex cis-diammineplatinum(II)-chlorocholylglycinate (Bamet-R2) by the rat liver.
Rat liver uptake and bile output of the cytostatic complex cis-diammineplatinum(II)-chlorocholylglycinate (Bamet-R2) were studied. Up to 100 microM, Bamet-R2 uptake by rat hepatocytes in primary culture followed saturation kinetics (Vmax = 0.65 +/- 0.12 nmol/5 min per mg protein; K(M) = 45.2 +/- 10.7 microM). Bamet-R2 uptake was lower than that of cholylglycinate (CG) but higher than that of cisplatin. Replacement of 116 mM NaCl by 116 mM choline chloride did not significantly reduce Bamet-R2 uptake. Addition of 500 microM CG, cholic acid, estrone sulfate, or ouabain to 50 microM Bamet-R2-containing incubation media inhibited Bamet-R2 uptake. No liver biotransformation of Bamet-R2 occurred, as indicated by HPLC analysis of bile collected from anesthetized rats after intravenous administration of the drug. Bamet-R2 uptake and secretion into bile by isolated rat livers exceeded those of cisplatin but were lower than those of CG. Differences between Bamet-R2 and CG were more marked for bile output than for liver uptake. Thus, higher Bamet-R2 than CG or cisplatin liver content was found. Co-administration of Bamet-R2 and CG revealed that CG induced a slight reduction in Bamet-R2 uptake and a marked inhibition in Bamet-R2 bile output. By contrast, Bamet-R2 had no effect on CG on either liver uptake or bile output. In sum, the present data indicate that Bamet-R2 is efficiently taken up and secreted into bile by the rat liver by mechanisms shared in part by natural bile acids.
Macias
R I
RI
Department of Physiology and Pharmacology, School of Pharmacy, University of Salamanca, Campus Miguel de Unamuno, Spain.
Monte
M J
MJ
El-Mir
M Y
MY
Villanueva
G R
GR
Marin
J J
JJ
D000818:Animals; D000970:Antineoplastic Agents; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D001692:Biological Transport; D001711:Biotransformation; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D006000:Glycocholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C108271:diaminneplatinum(II)-chlorocholylglycinate; D006000:Glycocholic Acid; D002945:Cisplatin