RT Journal Article
SR Electronic
T1 Disposition of [<em>G</em>-<sup>3</sup>H]paclitaxel and Cremophor EL in a Patient with Severely Impaired Renal Function
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1300
OP 1305
VO 27
IS 11
A1 Hans Gelderblom
A1 Jaap Verweij
A1 Eric Brouwer
A1 Marrimuthoo Pillay
A1 Peter de Bruijn
A1 Kees Nooter
A1 Gerrit Stoter
A1 Alex Sparreboom
YR 1999
UL http://dmd.aspetjournals.org/content/27/11/1300.abstract
AB In the present work, we studied the pharmacokinetics and metabolic disposition of [G-3H]paclitaxel in a female patient with recurrent ovarian cancer and severe renal impairment (creatinine clearance: ∼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/m2 (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 μM.h (mean ± S.D.; n = 6; c.v. = 4.29%), and a terminal disposition half-life of ∼29 h. Both parameters are substantially increased (∼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 μl.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. The American Society for Pharmacology and Experimental Therapeutics