Probenecid alters topotecan (TPT) systemic and renal disposition

The effect of probenecid on the disposition of TPT lactone (LAC), hydroxy acid (HA), and total (TOT; sum of LAC and HA) was evaluated in mice. Both TPT and HA (1.25 mg/kg i.v.) were administered alone, and with p.o. probenecid 600 (P600) and 1200 mg/kg (P1200) 0.5 hours before and 3 hours after. Serial plasma and urine samples were collected and TPT and TOT measured by HPLC. HA was calculated as the difference between TOT and LAC. AUC (ng-hr/mL) and clearance (CL; L/hr/m²) were estimated from compartmental parameters, and TPT renal CL was calculated. After TPT, P600 reduced TOT renal CL by 50%. Administration TPT TPT TPT HA HA Treatment Alone P600 P1200 Alone P600 LAC AUC 223.1 278.5 319.2 n/a n/a HA AUC n/a n/a n/a 356.0 1297.2 TOT AUC 332.7 511.7 554.8 391.7 1386.9 TPT CL 16.3 13.6 11.8 n/a n/a HA CL n/a n/a n/a 8.8 2.8 These data suggest probenecid primarily inhibits HA renal tubular secretion and increases TPT systemic exposure.