The renal clearance of unchanged cisplatin during furosemide and mannitol diuresis is dependent on glomerular filtration rate in rats.
The disposition of unchanged cisplatin (CDDP) in plasma and urine after bolus injection of CDDP (5 mg/kg) was compared in rats treated with furosemide (25 mg/kg as a 40-min iv infusion) and mannitol (2 g/kg as a 40-min iv infusion). Forced diuresis significantly increased renal clearance (Clr) of unchanged CDDP in the first 10-min period after CDDP administration, compared to that in the rats given CDDP alone. Compared with furosemide, mannitol showed greater modification in Clr of unchanged CDDP in the early phase and more accelerated urinary excretion of unchanged CDDP during the study. Furosemide increased plasma concentration and reduced urinary excretion of unchanged CDDP in the terminal phase. Clr of unchanged CDDP was found to be dependent of glomerular filtration rate (GFR) during diuretic coadministration. Linear relationships among urine flow rate, GFR, and Clr of unchanged CDDP were observed only in diuretic-treated rats. Although the relationships between GFR and Clr were almost identical, there was a difference in the GFR-urine flow rate relationship between furosemide- and mannitol-treated rats. GFR was gradually reduced during diuretic treatment, and furosemide induced greater GFR reduction than mannitol. This resulted in a modification of unchanged CDDP disposition by furosemide in the terminal phase. The present study suggests that careful monitoring and maintaining of GFR during coadministration of diuretic may be useful for predicting the urinary excretion behavior of unchanged CDDP in CDDP chemotherapy.
Nagai
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N
Department of Biopharmaceutics, Meiji College of Pharmacy, Tokyo, Japan.
Ogata
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H
D000818:Animals; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000652:urine; D004232:Diuretics / Q000494:pharmacology*; D004234:Diuretics, Osmotic / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology*; D005919:Glomerular Filtration Rate; D008297:Male; D008353:Mannitol / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D004232:Diuretics; D004234:Diuretics, Osmotic; D008353:Mannitol; D005665:Furosemide; D002945:Cisplatin