New estradiol-linked nitrosoureas: can the pharmacokinetic properties help to explain the pharmacodynamic activities?
The pharmacokinetics of 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) a new estradiol-linked anticancer drug and the unlinked DNA-crosslinking agent 1-(2-chloroethyl)-1-nitrosocarbamoyl-L-alanine (CNC-alanine) have been studied in methylnitrosourea-induced female Sprague-Dawley rats after equimolar intravenous and oral administration. In comparison with the unlinked single agent, the CNC-alanine-estradiol-17-ester showed a 3-fold longer halflife in plasma and a three times larger volume of distribution. The distribution after intravenous administration was nearly three times faster. The absorption after peroral administration was likewise two times faster. The bioavailability of the estradiol-linked drug was determined to be 52%. After application of CNC-alanine-estradiol-17-ester the cytostatic metabolite CNC-alanine was found, indicating the cleavage of the ester bond. CNC-alanine generated from CNC-alanine-estradiol-17-ester showed a 50% longer halflife than when applied directly. The results indicate that linking 2-chloroethyl-nitrosoureas to estradiol can result in new anticancer agents with modified properties in comparison to the unlinked single agent. The higher antineoplastic activity of the hormone-linked drug can mainly be attributed to differences in the pharmacokinetic behaviour.
Betsch
B
B
Institute for Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg.
Berger
M R
MR
Spiegelhalder
B
B
Eisenbrand
G
G
Schmähl
D
D
D000284:Administration, Oral; D000409:Alanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004958:Estradiol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D005260:Female; D007275:Injections, Intravenous; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism; D009588:Nitrogen Mustard Compounds / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D004958:Estradiol; C058788:N-(2-chloroethyl)-1-nitrosocarbamoylalanine; C056364:1-(2-chloroethyl)-1-nitrosocarbamoylalanine estradiol-17-ester; D000409:Alanine