Disposition of [G-(3)H]paclitaxel and cremophor EL in a patient with severely impaired renal function
In the present work, we studied the pharmacokinetics and metabolic disposition of [G-(3)H]paclitaxel in a female patient with recurrent ovarian cancer and severe renal impairment (creatinine clearance: approximately 20 ml/min) due to chronic hypertension and prior cisplatin treatment. During six 3-weekly courses of paclitaxel at a dose level of 157.5 mg/m(2) (viz. a 10% dose reduction), the renal function remained stable. Pharmacokinetic evaluation revealed a reproducible and surprisingly high paclitaxel area under the plasma concentration-time curve of 26.0 +/- 1.11 microM.h (mean +/- S.D.; n = 6; c.v. = 4.29%), and a terminal disposition half-life of approximately 29 h. Both parameters are substantially increased ( approximately 1.5-fold) when compared with kinetic data obtained from patients with normal renal function. The cumulative urinary excretion of the parent drug was consistently low and averaged 1.58 +/- 0.417% (+/- S.D.) of the dose. Total fecal excretion (measured in one course) was 52.9% of the delivered radioactivity, and mainly comprised known mono- and dihydroxylated metabolites, with unchanged paclitaxel accounting for only 6.18%. The plasma area under the plasma concentration-time curve of the paclitaxel vehicle Cremophor EL, which can profoundly alter the kinetics of paclitaxel, was 114.9 +/- 5.39 microl.h/ml, and not different from historic data in patients with normal or mild renal dysfunction. Urinary excretion of Cremophor EL was less than 0.1% of the total amount administered. These data indicate that the substantial increase in systemic exposure of the patient to paclitaxel relates to decreased renal metabolism and/or urinary elimination of polar radioactive species, most likely lacking an intact taxane ring fragment.
|Keywords||Aged, Antineoplastic Agents, Phytogenic/blood/*pharmacokinetics/therapeutic use, Chromatography, High Pressure Liquid, Female, Glycerol/*analogs & derivatives/pharmacokinetics, Humans, Nephrosclerosis/complications/*metabolism/physiopathology, Ovarian Neoplasms/complications/drug therapy, Paclitaxel/blood/*pharmacokinetics/therapeutic use, Spectrophotometry, Ultraviolet|
Gelderblom, A.J., Verweij, J., Brouwer, E., Pillay, M., de Bruijn, P., Nooter, K., … Sparreboom, A.. (1999). Disposition of [G-(3)H]paclitaxel and cremophor EL in a patient with severely impaired renal function. Drug Metabolism and Disposition: the biological fate of chemicals. Retrieved from http://hdl.handle.net/1765/9184