Effect of time of cisplatin administration on its toxicity and pharmacokinetics in dogs

Elizabeth M. Hardie From the Departments of Companion Animal and Special Species Medicine (Hardie, Page, Fischer) and Anatomy, Physiological Sciences, and Radiology (Williams), College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St, Raleigh, NC 27606.

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 DVM, PhD
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Rodney L. Page From the Departments of Companion Animal and Special Species Medicine (Hardie, Page, Fischer) and Anatomy, Physiological Sciences, and Radiology (Williams), College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St, Raleigh, NC 27606.

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 DVM, MS
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Patrick L. Williams From the Departments of Companion Animal and Special Species Medicine (Hardie, Page, Fischer) and Anatomy, Physiological Sciences, and Radiology (Williams), College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St, Raleigh, NC 27606.

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W. D. Fischer From the Departments of Companion Animal and Special Species Medicine (Hardie, Page, Fischer) and Anatomy, Physiological Sciences, and Radiology (Williams), College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough St, Raleigh, NC 27606.

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SUMMARY

Cisplatin (90 mg/m2) was administered in a 5-minute bolus iv infusion to dogs at 8 am (n = 6) or 4 pm (n = 6). Blood and urine samples were collected over a 4-hour period for statistical moment pharmacokinetic analysis. Mean urinary excretion rate of total platinum was increased, whereas mean plasma residence time of ultrafilterable platinum was decreased, in the group treated at 4 pm (pm group), compared with those treated at 8 am (am group). Over a 2-week postinfusion-monitoring period, both groups of dogs developed decreases in creatinine clearance, urine/serum osmolality ratio (UOsm/SOsm), specific gravity, and increase in bun, serum creatinine concentration, urine γ-glutamyltranspeptidase/urine creatinine ratio (UGGT/UCr), fractional excretion of magnesium, and fractional excretion of phosphate. Urine specific gravity and UOsm/SOsm were significantly decreased, whereas UGGT/UCr and bun were significantly increased in the am group, compared with the pm group. The time of administration had a significant effect on the pharmacokinetics of cisplatin, which resulted in significant differences in cisplatin-induced renal toxicosis.

SUMMARY

Cisplatin (90 mg/m2) was administered in a 5-minute bolus iv infusion to dogs at 8 am (n = 6) or 4 pm (n = 6). Blood and urine samples were collected over a 4-hour period for statistical moment pharmacokinetic analysis. Mean urinary excretion rate of total platinum was increased, whereas mean plasma residence time of ultrafilterable platinum was decreased, in the group treated at 4 pm (pm group), compared with those treated at 8 am (am group). Over a 2-week postinfusion-monitoring period, both groups of dogs developed decreases in creatinine clearance, urine/serum osmolality ratio (UOsm/SOsm), specific gravity, and increase in bun, serum creatinine concentration, urine γ-glutamyltranspeptidase/urine creatinine ratio (UGGT/UCr), fractional excretion of magnesium, and fractional excretion of phosphate. Urine specific gravity and UOsm/SOsm were significantly decreased, whereas UGGT/UCr and bun were significantly increased in the am group, compared with the pm group. The time of administration had a significant effect on the pharmacokinetics of cisplatin, which resulted in significant differences in cisplatin-induced renal toxicosis.

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