![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vol. 284, Issue 1, 89-94, 1998
Departments of
Pharmaceutical Sciences (W.C.Z., J.L.H., W.R.C.,
S.K.H, C.F.S.),
Molecular Pharmacology (P.J.H., P.J.C., L.B.R.) and
Biostatistics (X.L.), St. Jude Children's Research Hospital;
Department of Pharmacology (P.J.H.),
University of Tennessee, Memphis,
SmithKline Beecham (R.K.J.), King of Prussia, Pennsylvania, and
The
Center for Pediatric Pharmacokinetics and Therapeutics (C.F.S.),
University of Tennessee, Memphis, Tennessee
Topotecan is primarily eliminated by the kidneys, with 60 to 70% of
the dose recovered as topotecan total in the urine. To elucidate the
mechanisms of topotecan renal clearance, we evaluated the effect of
probenecid on topotecan renal and systemic disposition in mice.
Topotecan lactone or hydroxy acid (1.25 mg/kg i.v.) was administered
alone or in combination with probenecid (600 or 1200 mg/kg) given by
oral gavage 30 min before and 3 hr after topotecan. Serial blood
samples (three mice per time point) and urine samples (five mice per
treatment arm) were collected during a 6-hr period. Compared with
topotecan alone, coadministration of topotecan lactone or hydroxy acid
with probenecid (600 mg/kg) decreased topotecan lactone, total, and
hydroxy acid systemic clearance, and total renal clearance. The
predominant effect of probenecid was to increase hydroxy acid area
under the plasma concentration time curve after administration of
topotecan lactone (238.8 vs. 109.9 ng·hr/ml alone,
P < .05), or hydroxy acid (1297.2 vs. 355.0 ng·hr/ml alone, P < .05). By inhibiting renal tubular
secretion, probenecid decreased renal and systemic clearance which led
to an increase in topotecan systemic exposure. These data suggest that
probenecid primarily inhibited secretion of the anionic hydroxy acid
form, and by direct or indirect mechanisms increased topotecan lactone
systemic exposure. Topotecan elimination through renal tubular
secretion may have clinical relevance for the use of topotecan in
patients with altered renal function.
This article has been cited by other articles:
|
|
 |
|
  P. Schaiquevich, J. C. Panetta, L. C. Iacono, B. B. Freeman III, V. M. Santana, A. Gajjar, and C. F. Stewart Population Pharmacokinetic Analysis of Topotecan in Pediatric Cancer Patients Clin. Cancer Res., November 15, 2007; 13(22): 6703 - 6711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. de Vries, J. Zhao, E. Kroon, T. Buckle, J. H. Beijnen, and O. van Tellingen P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan Clin. Cancer Res., November 1, 2007; 13(21): 6440 - 6449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-i. Matsumoto, K. Yoshida, N. Ishiguro, T. Maeda, and I. Tamai Involvement of Rat and Human Organic Anion Transporter 3 in the Renal Tubular Secretion of Topotecan [(S)-9-Dimethylaminomethyl-10-hydroxy-camptothecin hydrochloride] J. Pharmacol. Exp. Ther., September 1, 2007; 322(3): 1246 - 1252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Metzger, C. F. Stewart, B. B. Freeman III, C. A. Billups, F. A. Hoffer, J. Wu, M. J. Coppes, R. Grant, M. Chintagumpala, E. A. Mullen, et al. Topotecan Is Active Against Wilms' Tumor: Results of a Multi-Institutional Phase II Study J. Clin. Oncol., July 20, 2007; 25(21): 3130 - 3136. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Santana, W. L. Furman, C. A. Billups, F. Hoffer, A. M. Davidoff, P. J. Houghton, and C. F. Stewart Improved Response in High-Risk Neuroblastoma With Protracted Topotecan Administration Using a Pharmacokinetically Guided Dosing Approach J. Clin. Oncol., June 20, 2005; 23(18): 4039 - 4047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Zhang, X. Wang, K. Sagawa, and M. E. Morris FLAVONOIDS CHRYSIN AND BENZOFLAVONE, POTENT BREAST CANCER RESISTANCE PROTEIN INHIBITORS, HAVE NO SIGNIFICANT EFFECT ON TOPOTECAN PHARMACOKINETICS IN RATS OR MDR1A/1B (-/-) MICE Drug Metab. Dispos., March 1, 2005; 33(3): 341 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Leggas, M. Adachi, G. L. Scheffer, D. Sun, P. Wielinga, G. Du, K. E. Mercer, Y. Zhuang, J. C. Panetta, B. Johnston, et al. Mrp4 Confers Resistance to Topotecan and Protects the Brain from Chemotherapy Mol. Cell. Biol., September 1, 2004; 24(17): 7612 - 7621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. M. Santana, W. C. Zamboni, M. N. Kirstein, M. Tan, T. Liu, A. Gajjar, P. J. Houghton, and C. F. Stewart A Pilot Study of Protracted Topotecan Dosing Using a Pharmacokinetically Guided Dosing Approach in Children with Solid Tumors Clin. Cancer Res., February 1, 2003; 9(2): 633 - 640. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. L. Furman, C. F. Stewart, M. Kirstein, J. L. Kepner, M. L. Bernstein, F. Kung, T. J. Vietti, C. P. Steuber, D. L. Becton, S. Baruchel, et al. Protracted Intermittent Schedule of Topotecan in Children With Refractory Acute Leukemia: A Pediatric Oncology Group Study J. Clin. Oncol., March 15, 2002; 20(6): 1617 - 1624. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Montazeri, S. Culine, B. Laguerre, F. Pinguet, F. Lokiec, N. Albin, A. Goupil, R. Deporte-Fety, R. Bugat, P. Canal, et al. Individual Adaptive Dosing of Topotecan in Ovarian Cancer Clin. Cancer Res., February 1, 2002; 8(2): 394 - 399. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
