TY - JOUR 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 SP - 1300 LP - 1305 VL - 27 IS - 11 AU - Hans Gelderblom AU - Jaap Verweij AU - Eric Brouwer AU - Marrimuthoo Pillay AU - Peter de Bruijn AU - Kees Nooter AU - Gerrit Stoter AU - Alex Sparreboom Y1 - 1999/11/01 UR - http://dmd.aspetjournals.org/content/27/11/1300.abstract N2 - 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 ER -