Urinary and fecal excretion of topotecan in patients with malignant solid tumours

Herben, V. M. M.; Schoemaker, Nadja E.; Rosing, Hilde; Zomeren, D. M. Van Gortel-Van; Huinink, W.W. ten Bokkel; Dubbelman, R.; Hearn, Solange; Schellens, Jan H.M.; Beijnen, Jos H.

doi:10.1007/s00280-002-0454-2

Cited by 31 publications

(19 citation statements)

References 18 publications

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“…In patients with normal renal function, topotecan is mainly eliminated by renal excretion, with approximately half of the administered intravenous dose excreted as parent drug in the urine [10]. Recently, pharmacokinetic studies in patients with impaired renal function showed that reduction of topotecan dosages in patients from 1.5 to 0.75 mg/m 2 resulted in adequate topotecan levels [11].…”

Section: Discussionmentioning

confidence: 99%

Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

Lugtenberg

Cransberg

Loos

et al. 2008

Cancer Chemother Pharmacol

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The therapeutic strategy for bilateral Wilms tumor (WT) remains a challenge. Especially in cases with chemotherapy resistant disease, bilateral nephrectomy is sometimes inevitable. For optimal cure rates stage V WT patients beneWt from adjuvant treatment; however, there are limited data available on chemotherapy pharmacokinetics in anephric children. In this report, we describe a 10-month old girl with bilateral Wilms tumor and a novel germline WT1 gene mutation. This patient hardly showed any response on preoperative chemotherapy, and ultimately, underwent sequential bilateral tumor-nephrectomy. Subsequently, during peritoneal dialysis, she received topotecan as adjuvant chemotherapy based on plasma levels, indicating that this is a reasonable option as adjuvant treatment in therapy-resistant Wilms tumor patients after bilateral nephrectomy. This case showed a novel germline WT1 gene mutation of which the correlation with resistant phenotype has to be conWrmed in larger cohorts of WT patients.

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Section: Discussionmentioning

confidence: 99%

Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

Lugtenberg

Cransberg

Loos

et al. 2008

Cancer Chemother Pharmacol

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“…in cancer patients (Herben et al, 2002). Although topotecan undergoes both renal and hepatobiliary excretion (Stewart et al, 1994;Furman et al, 1996), it has been shown to undergo only limited metabolism (Herben et al, , 2002Rosing et al, 1997). A population pharmacokinetic analysis indicated that tubular secretion in addition to glomerular filtration is involved in topotecan renal clearance in humans (Mould et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Topotecan is primarily excreted into urine as both lactone and hydroxyl acid forms, accounting for approximately 49% of the dose administered i.v. in cancer patients (Herben et al, 2002). Although topotecan undergoes both renal and hepatobiliary excretion (Stewart et al, 1994;Furman et al, 1996), it has been shown to undergo only limited metabolism (Herben et al, , 2002Rosing et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…Many investigators have reported on the systemic and renal disposition of topotecan in various animals and humans (Herben et al, 1996(Herben et al, , 2002Zamboni et al, 1998;Hartmann and Lipp, 2006;Mustafa et al, 2006). Topotecan is primarily excreted into urine as both lactone and hydroxyl acid forms, accounting for approximately 49% of the dose administered i.v.…”

Section: Discussionmentioning

confidence: 99%

“…It is primarily excreted in urine with both topotecan lactone and the hydroxyl acid form, accounting for approximately 49% of the administered i.v. dose in cancer patients (Herben et al, 2002). In a study of adults with normal (creatinine clearance, 64 -171 ml/min) and impaired renal function (creatinine clearance, 18 -59 ml/min), renal clearance of topotecan was decreased in patients with renal dysfunction (O'Reilly et al, 1996a).…”

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Involvement of Rat and Human Organic Anion Transporter 3 in the Renal Tubular Secretion of Topotecan [(S)-9-Dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride]

Matsumoto

Yoshida²,

Ishiguro³

et al. 2007

J Pharmacol Exp Ther

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Topotecan [(S)-9-dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride] is primarily excreted into urine in humans, with approximately 49% of the dose recovered as total topotecan (topotecan lactone plus topotecan hydroxyl acid form). The renal elimination of topotecan involves tubular secretion in addition to glomerular filtration, but little is known about the molecular mechanism of the renal tubular secretion. In the present study, we investigated the transport characteristics of topotecan hydroxyl acid across the renal basolateral membrane using rat kidney slices and rat or human transporterexpressing Xenopus laevis oocytes. Pravastatin and probenecid significantly inhibited the uptake of topotecan hydroxyl acid by rat kidney slices with K i values of 10.6 and 8.1 M, respectively, and p-aminohippurate was weakly inhibitory at high concentrations, whereas excess tetraethylammonium had no effect. The uptake of topotecan hydroxyl acid by oocytes injected with complementary RNA of either rat or human organic anion transporter 3 (rOAT3 or hOAT3) was greater than that of waterinjected oocytes. Kinetic analysis showed that the K m values for rOAT3 and hOAT3 were 21.9 and 56.5 M, respectively. Neither rOAT1 nor hOAT1 stimulated topotecan hydroxyl acid transport. These results suggest that the urinary excretion of topotecan hydroxyl acid is accounted for by transport via OAT3, as well as glomerular filtration, in both rats and humans; therefore, drug-drug interactions involving OAT3 may cause a change in clearance of topotecan.

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Determination of topotecan in human and mouse plasma and in mouse tissue homogenates by reversed‐phase high‐performance liquid chromatography

Vries

Ouwehand

Buckle

et al. 2007

Biomedical Chromatography

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A sensitive and selective reversed-phase high-performance liquid chromatographic (HPLC) assay has been developed and validated for quantification of total topotecan in human and mouse plasma and in mouse tissue samples. Isocratic separation was achieved on a Zorbax SB-C(18) column and topotecan was monitored fluorimetrically. Two ranges of calibrations curves were used to determine lower levels of topotecan more accurately. Acceptable accuracy and precision was achieved for all matrices. Topotecan was stable upon repeated freeze-thawing for three cycles or storage for 24 h at ambient temperatures in spiked plasma samples and tissue homogenates, except in heart homogenates. In an additional validation experiment in which (14)C-labeled topotecan was administered to mice, the levels of unchanged topotecan were about 80-90% of the total radioactivity in tissue homogenates collected 10 min after drug administration and virtually similar as in plasma samples. However, results in tissue homogenates obtained 4 h post-drug administration indicated substantial metabolism of topotecan. This assay is suitable for studying the pharmacokinetics and tissue distribution of topotecan in mice. Our results demonstrate the importance of including all tissues of interest for pharmacokinetic studies in the validation procedure.

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Urinary and fecal excretion of topotecan in patients with malignant solid tumours

Abstract: Fecal and urinary excretion of unchanged topotecan were the major routes of topotecan elimination. Approximately 28% of the intravenous dose and 43% of the oral dose of topotecan were unaccounted for and eliminated through other routes.

Cited by 31 publications

References 18 publications

Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

Involvement of Rat and Human Organic Anion Transporter 3 in the Renal Tubular Secretion of Topotecan [(S)-9-Dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride]

Determination of topotecan in human and mouse plasma and in mouse tissue homogenates by reversed‐phase high‐performance liquid chromatography

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