Clinical pharmacology of CPT-11 and topotecan is now relatively well developed. Both can be absorbed orally, with topotecan bioavailability of 30-50%; both are widely distributed throughout the body, with cerebrospinal fluid topotecan concentrations 30-50% of simultaneous plasma concentrations.
Topotecan undergoes negligible metabolism. CPT-11 is in itself relatively inactive and must be converted by carboxylesterases to SN-38 that has potent topol inhibitory activity. SN-38 undergoes glucuronidation to inactive metabolite by uridine-diphosphosphate glucuronosylatransferase lAl and genetic polymorphism in the formation of SN-38 glucuronide has been proposed.
Topotecan is primarily eliminated by the kidneys, with evidence for renal tubular secretion. A linear relationship between creatinine clearance and clearance of both total topotecan and lactone form has been demonstrated. Approximately 20% of the total dose of CPT-11 is excreted unchanged in urine, whereas less than 1% is excreted as SN-38. Glucuronidation and biliary excretion appear to be principal mechanisms of elimination for SN-38.
Several mechanisms of resistance to topol inhibitors have been described in in vitro systems. These include:
♦ Factors that affect the stabilization of the topol-DNA complex
♦ Alterations in drug accumulation
♦ Decreased activation of CPT-11
♦ Decreased cellular content/activity of topol
♦ Mutations of the topo I enzyme
Little is know about mechanisms of resistance to CPT or its analogues in human tumours.
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