Pharmacokinetic behaviour of the chemoprotectants BNP7787 and mesna after an i.v. bolus injection in rats.
In preclinical studies, BNP7787 (disodium 2,2'-dithio-bis-ethane sulphonate), the disulphide form of mesna, has demonstrated selective protection against cisplatin-induced nephrotoxicity due to conversion into mesna inactivating toxic platinum species. Mesna (sodium 2-mercapto ethane sulphonate), however, can affect the antitumour activity of cisplatin, while BNP7787 does not interfere with the antitumour activity. To understand the difference in interference with cisplatin-induced antitumour activity between BNP7787 and mesna as well to characterise the selective nephroprotection by BNP7787, the pharmacokinetics of BNP7787 and mesna, each given i.v. 1000 mg x kg(-1), were determined in plasma, kidney, liver, red blood cells (RBC), skeletal muscle and tumour of Fischer rats bearing subcutaneously implanted WARD colon tumours. The following results were obtained: (1). high concentrations of BNP7787 and mesna were observed in the plasma and kidney after administration of BNP7787 or mesna, except for mesna in plasma after BNP7787 administration; (2). in all other sampled compartments, the AUC values of both compounds were at least 5.5-fold lower than the corresponding values in kidney; (3). the AUC of mesna in plasma after mesna administration was comparable to the AUC of mesna in kidney after a dose of BNP7787 that can completely prevent cisplatin-induced nephrotoxicity in rats; (4). the AUC of mesna in plasma was five-fold higher relative to the AUC of mesna following BNP7787 administration (P<0.01). In conclusion, the five-fold higher AUC of mesna in plasma after mesna administration and the fact that mesna is more reactive with (hydrated) cisplatin than its disulphide form BNP7787 represent a plausible explanation as to why mesna administration can reduce the antitumour activity of cisplatin. After BNP7787 administration, the distribution of BNP7787 and mesna was restricted to the kidney, which confirmed the selective protection of the kidney by BNP7787.
Verschraagen
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Department of Medical Oncology, Vrije Universiteit Medical Center, De Boelelaan 1117, 1007 MB Amsterdam, The Netherlands.
Boven
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Torun
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Erkelens
C A M
CA
Hausheer
F H
FH
van der Vijgh
W J F
WJ
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D002945:Cisplatin / Q000009:adverse effects*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000662:veterinary; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D015080:Mesna / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D009374:Neoplasms, Experimental; D020011:Protective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344
D000970:Antineoplastic Agents; D020011:Protective Agents; C027032:2,2'-dithiodiethanesulfonic acid; D015080:Mesna; D002945:Cisplatin