Rat liver transport and biotransformation of a cytostatic complex of bis-cholylglycinate and platinum (II).
OBJECTIVE
Bile acids have previously been used as shuttles for directing organic drugs to the liver. The aim of this study was to investigate liver transport and biotransformation of a new cytostatic bioinorganic complex (Bamet-H2), that was obtained by binding platinum(II) to two cholylglycinate moieties.


METHODS
Using rat hepatocytes in primary culture, the kinetics of cholylglycinate, cisplatin and Bamet-H2 uptake were studied. Sodium-dependency of Bamet-H2 uptake was investigated by replacement of 116 mM NaCl by 116 mM choline chloride. Liver biotransformation was investigated by HPLC analysis of bile samples collected from anesthetized rats following intravenous Bamet-H2 administration. Using isolated rat liver preparations, which were perfused with erythrocyte- and albumin-free Krebs-Henseleit solutions for 40 min, measurement of cholylglycinate, cisplatin and Bamet-H2 uptake and bile output was carried out. Interaction between Bamet-H2 and cholylglycinate for liver transport was studied by co-administration of 1 microM Bamet-H2 plus 500 microM cholylglycinate and 1 microM [14C]-cholylglycinate plus 500 microM Bamet-H2.


RESULTS
Both cholylglycinate and Bamet-H2 uptake by rat hepatocytes followed saturation kinetics. Comparison between the two compounds indicated that the Vmax (22.2 versus 8.5 nmol.5 min(-1).mg protein(-1)), and Kt (365 versus 171 microM) were higher for Bamet-H2 uptake. The efficiency of Bamet-H2 uptake (Vmax/Kt) was significantly reduced (-35%) in the absence of sodium. Cisplatin uptake by rat hepatocytes was approximately 10-fold lower than that for Bamet-H2 at any dose used. Moreover, this was not saturable up to 400 microM cisplatin. Bamet-H2 was not biotransformed during its intrahepatic residence in anesthetized rats. Bamet-H2 uptake and secretion into bile by isolated rat livers exceeded cisplatin but were less than cholylglycinate. Differences between Bamet-H2 and cholylglycinate were more marked for bile output than for liver uptake. Thus, higher drug liver content was found after perfusion with Bamet-H2 than with cholylglycinate or cisplatin. Co-administration of Bamet-H2 and cholylglycinate revealed the existence of partial cross-inhibition in both liver uptake and bile output. Bamet-H2 induced a more profound alteration on cholylglycinate uptake and bile secretion than cholylglycinate on both process for Bamet-H2.


CONCLUSIONS
These results suggest that in the transfer of Bamet-H2 from the sinusoids to the canaliculi both bile acid and non-bile acid transport systems are involved.
Marin
J J
JJ
Department of Physiology and Pharmacology, School of Pharmacy, University of Salamanca, Spain. jjgmarin@gugu.usal.es
Herrera
M C
MC
Palomero
M F
MF
Macias
R I
RI
Monte
M J
MJ
El-Mir
M Y
MY
Villanueva
G R
GR
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000502:physiology; D001711:Biotransformation / Q000502:physiology; D002478:Cells, Cultured; D002945:Cisplatin / Q000493:pharmacokinetics; D006000:Glycocholic Acid / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D009942:Organometallic Compounds / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
D009942:Organometallic Compounds; C112413:bamet H2; D006000:Glycocholic Acid; D002945:Cisplatin