Macromolecular prodrug that provides the irinotecan (CPT-11) active-metabolite SN-38 with ultralong half-life, low C(max), and low glucuronide formation.
We have recently reported a chemical approach for half-life extension that utilizes β-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol-containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied.
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Daniel V
DV
Santi
Eric L
EL
Schneider
Gary W
GW
Ashley
D000588:Amines / Q000737:chemistry; D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations; D005260:Female; D020719:Glucuronides / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D046911:Macromolecular Substances; D010636:Phenols / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000588:Amines; D003692:Delayed-Action Preparations; D020719:Glucuronides; D046911:Macromolecular Substances; D010636:Phenols; D011355:Prodrugs; D002166:Camptothecin