Topotecan metabolism

They cause substantial DNA damage in tumor cells, preventing tumor growth. Topotecan has been evaluated in metastatic ovarian cancer. Irinotecan is a prodrug that is metabolized to a topoisomerase I inhibitor it has been used in the treatment of colon and... 

DOCETAXEL TOPOTECAN t risk of neutropenia when topotecan is administered on days 1-4 and docetaxel on day 4 Attributed to 1 clearance of docetaxel (by 50%) due to inhibition of hepatic metabolism of docetaxel by CYP3A4 by topotecan Administer docetaxel on day 1 and topotecan on days 1-4... 

TOPOTECAN ANTIEPILEPTICS-PHENYTOIN 1 efficacy of topotecan due to t plasma concentrations of topotecan lactone and its metabolites by 1.5 Due to induction of further metabolism by hepatic CYP3A4 by phenytoin t dose of topotecan to obtain desired therapeutic results... 

Exatecan is a novel synthetic camptothecin derivative with a unique hexacyclic structure. It does not require metabolic activation, whereas irinotecan does. In vitro experiments in various cell lines have suggested that exatecan may be 6 and 28 times more active than SN-38 (7-ethyl-lO-hydroxycamptothecin, the active metabolite of irinotecan) and topotecan respectively. Furthermore, it has a 2-10 times higher therapeutic index than irinotecan and topotecan. In addition, exatecan may even be active in P-glycoprotein-mediated multidrug-resistant tumor cells. Its dose-limiting adverse effects are neutropenia and liver dysfunction. The recommended dosages of exatecan for phase II trials are 0.5 mg/m /day or 0.3 mg/ m /day as a 30-minute infusion on 5 consecutive days for minimally pretreated and heavily pretreated patients respectively (14,15). 

Hepatic metabolism of topotecan, mediated by cytochrome P450 isozymes, is of minor quantitative importance (26-29,58). Metabolic pathways include N-dealkylation (producing A-demethyltopotecan) and glucuronidation. There is some evidence that potent inhibitors or inducers of CYP3A4 alter the clearance of topotecan (58). 

Metabolism/elimination Topotecan primarily renal clearance Irinotecan converted to active metaboirte in the liver Renal and nonrenal clearance... 

In contrast to topotecan, hepatic metabolism represents an important route of elimination for both irinotecan and SN-38. Several oxidative metabolites have been identified in plasma, all of which result from CYP3A-mediated reactions directed at the bispiperidine side chain. These metabolites are not significantly converted to SN-38. The total body clearance of irinotecan was found to be two times greater in brain cancer patients who were concurrently taking antiseizure drugs that induce hepatic CYPs, further attesting to the importance of oxidative hepatic metabolism as a route of elimination for this drug. 

Topotecan elimination is biphasic, with a terminal half-life of 2.0 to 3.5 hours. Lactone hydrolysis is rapid, and binding to serum proteins is limited to between 25 and 40%. CYP3A4-mediated N-dealkylation to mono-and didealkylated metabolites occurs to a limited extent, and the 0-glucuronides that form at multiple points along the metabolic path are excreted via the kidney (Fig. 42.41). Extensive renal clearance demands dosage adjustment in patients with kidney disease. 

Because both topotecan and irinotecan are metabolized by CYP3A4, the potential for drug-drug interactions must be evaluated. Reduced clearance was noted when azole antifungal agents and cyclosporine were coadministered with irinotecan, and accelerated clearance... 

The novel DNA topoisomerase I inhibitor, DX-8951f (exatecan mesylate, 264) which does not require metabolic activation is fluorinated, hexacyclic derivative of camptothecin. Compound 264 was reported to be 6- and 28-fold more potent than SN-38 and topotecan, respectively.Compound 264 has shown efficacy in a variety of human mmor xenografts. 

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