title: Probenecid alters topotecan systemic and renal disposition by inhibiting renal tubular secretion.
abstract: 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 1,200 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.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Zamboni
authors.forename: P J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: R K
authors.initials: RK
authors.lastname: Johnson
authors.forename: J L
authors.initials: JL
authors.lastname: Hulstein
authors.forename: W R
authors.initials: WR
authors.lastname: Crom
authors.forename: P J
authors.initials: PJ
authors.lastname: Cheshire
authors.forename: S K
authors.initials: SK
authors.lastname: Hanna
authors.forename: L B
authors.initials: LB
authors.lastname: Richmond
authors.forename: X
authors.initials: X
authors.lastname: Luo
authors.forename: C F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D005260:Female; D007684:Kidney Tubules / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D011339:Probenecid / Q000494:pharmacology*; D012076:Renal Agents / Q000494:pharmacology*; D019772:Topotecan / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D012076:Renal Agents; D019772:Topotecan; D011339:Probenecid