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Research ArticleArticle

Disposition of [G-3H]paclitaxel and Cremophor EL in a Patient with Severely Impaired Renal Function

Hans Gelderblom, Jaap Verweij, Eric Brouwer, Marrimuthoo Pillay, Peter de Bruijn, Kees Nooter, Gerrit Stoter and Alex Sparreboom
Drug Metabolism and Disposition November 1999, 27 (11) 1300-1305;
Hans Gelderblom
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Jaap Verweij
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Eric Brouwer
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Marrimuthoo Pillay
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Peter de Bruijn
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Kees Nooter
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Gerrit Stoter
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Alex Sparreboom
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Abstract

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.

Footnotes

  • Send reprint requests to: Alex Sparreboom, Ph.D., Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, P.O. Box 5201, 3008 AE Rotterdam, the Netherlands. E-mail: sparreboom{at}onch.azr.nl

  • Abbreviations used are::
    AUC
    area under the plasma concentration-time curve
    • Received May 3, 1999.
    • Accepted July 28, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (11)
Drug Metabolism and Disposition
Vol. 27, Issue 11
1 Nov 1999
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Research ArticleArticle

Disposition of [G-3H]paclitaxel and Cremophor EL in a Patient with Severely Impaired Renal Function

Hans Gelderblom, Jaap Verweij, Eric Brouwer, Marrimuthoo Pillay, Peter de Bruijn, Kees Nooter, Gerrit Stoter and Alex Sparreboom
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1300-1305;

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Research ArticleArticle

Disposition of [G-3H]paclitaxel and Cremophor EL in a Patient with Severely Impaired Renal Function

Hans Gelderblom, Jaap Verweij, Eric Brouwer, Marrimuthoo Pillay, Peter de Bruijn, Kees Nooter, Gerrit Stoter and Alex Sparreboom
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1300-1305;
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