A comparative binding of platinum anti-tumour compounds to plasma proteins in the rat (in vivo) and mouse (in vitro).
Plasma protein binding of 195mPt-labelled cisplatin, carboplatin and iproplatin has been studied in vivo in rat and in vitro in mouse, using both electrophoresis and trichloroacetic acid precipitation. After intravenous injection plasma clearance rates were biphasic for all 3 compounds, (t1/2 alpha, 13-17 min) but cisplatin was retained thereafter longer than the others. By 5 min, gel electrophoresis showed protein labelling with all 3 drugs but none involved low mol.wt. proteins (< 16 kDa). At 2 h a notable proportion of the protein bound platinum was associated with the latter components. There was a general resemblance between the distribution patterns of cisplatin and carboplatin whereas iproplatin showed a persistent retention of the label with time to higher mol. wt. proteins. From in vitro incubation with mouse plasma, rates of interaction respectively were cisplatin t1/2 alpha, 35 min, beta 8 h, carboplatin t1/2, 44 h and iproplatin t1/2, 104 h. By electrophoresis the protein bound fraction pattern (1 h) was again similar for cisplatin and carboplatin with virtually no binding to low mol. wt. proteins. After 24 h these were now involved to a high degree (40%). Iproplatin showed relatively marked binding to proteins of higher mol. wt. but no transfer with time to the low mol. wt. protein zone. A possible explanation is the need for in vivo metabolism for this compound as manifest in the rat. It is suggested that the significance of interaction with low mol. wt. proteins merits further investigation in relation to the antitumour and toxicological actions of these drugs.
Perera
A
A
Department of Chemistry, University of Manchester Institute of Science and Technology, UK.
Jackson
H
H
Sharma
H L
HL
McAuliffe
C A
CA
Fox
B W
BW
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism*; D016190:Carboplatin / Q000378:metabolism / Q000493:pharmacokinetics; D002945:Cisplatin / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009944:Organoplatinum Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D010984:Platinum / Q000378:metabolism / Q000493:pharmacokinetics; D011485:Protein Binding; D011868:Radioisotopes; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001798:Blood Proteins; D009944:Organoplatinum Compounds; D011868:Radioisotopes; D010984:Platinum; C023359:iproplatin; D016190:Carboplatin; D002945:Cisplatin