Local distribution into brain tumor and pharmacokinetics of 4-pyridoxate diammine hydroxy platinum, a novel cisplatin derivative, after intracarotid administration in rats with 9L malignant glioma: simultaneous brain microdialysis study.
Local distribution into brain tumor and the pharmacokinetics of 4-pyridoxate diammine hydroxy platinum (PyPt), a novel cisplatin derivative, were examined using rats implanted with 9L glioma and compared with cisplatin. PyPt (5.0 mg/kg) and cisplatin (3.5 mg/kg) were administered as selective intracarotid infusions for 30 min to the rats. Dialysates from extracellular fluid (ECF) in tumor and non-tumor brain tissues were collected by simultaneous microdialysis. The amount of platinum was determined by atomic absorption spectrophotometry, as representative of the drug administered. Plasma concentration of total and protein unbound platinum, and urinary excretion amount and tissue distribution of total platinum were also determined. Unbound platinum was accumulated preferentially in the brain tumor tissue ECF after drug administration, while there was little distribution into normal tissue ECF of the brain. In the brain tumor, the values of the unbound platinum AUC and MRT, where AUC is the area under the concentration-time curve and MRT is the mean residence time, for PyPt were 1.7 and 1.3 times larger than with cisplatin, respectively. The brain tumor distribution coefficient (the ratio of brain tumor ECF platinum AUC to plasma protein unbound platinum AUC) for PyPt (0.85) was higher than that for cisplatin (0.69), indicating that the local amount of platinum distributed into the glioma is enhanced by PyPt rather than by cisplatin. The binding to plasma proteins of PyPt (23%) was lower than that of cisplatin (65%). The total platinum concentration in tissues after administration of PyPt was significantly lower than that of cisplatin in the kidney, liver and spleen. In addition, the urinary excretion amount of total platinum after the administration of PyPt was significantly larger than that of cisplatin. These results suggested that PyPt is easily eliminated by rapid urinary excretion because of its reduced interaction with plasma proteins and poor distribution to the kidney or reticuloendothelial tissues such as the liver and spleen. It is concluded that PyPt is an effective cisplatin derivative for the treatment of gliomas with the added advantage of enhancing local distribution of drug into the brain tumor and reducing its accumulation in the kidney, which has previously caused severe nephrotoxicity.
Tokunaga
Y
Y
Department of Neurosurgery, Nagasaki University School of Medicine, Japan. toku@net.nagasaki-u.ac.jp
Nakashima
M
M
Sasaki
H
H
Tomiyama
N
N
Nakashima
M N
MN
Ichikawa
M
M
Kaminogo
M
M
Shibata
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D002343:Carotid Artery, Internal; D002945:Cisplatin / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D005910:Glioma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D007261:Infusions, Intra-Arterial; D008297:Male; D017551:Microdialysis; D009368:Neoplasm Transplantation; D009944:Organoplatinum Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D010984:Platinum / Q000097:blood / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
C420692:4-pyridoxate diammine hydroxy platinum; D000970:Antineoplastic Agents; D001798:Blood Proteins; D009944:Organoplatinum Compounds; D010984:Platinum; D002945:Cisplatin