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Title	Comparative studies on selected alkyl ethers of p-N,N-bis (2- chloroethyl) aminophenol and of 4-N,N-bis (2-chloroethyl) amino-o-cresol : pharmacokinetic parameters and metabolic profiles
Author	Udo, David George
Date	1989
Affiliation/College	College of Graduate Studies
Department	Pharmaceutical Sciences
Extent	ix, 217 leaves; 29 cm
Source	QV 269 U21c 1989
Subject.MeSH	Alkylating Agents--pharmacokinetics Alkylating Agents--metabolism Academic Dissertations
Collection	MUSC Theses and Dissertations
Contributing Institution	Waring Historical Library (MUSC)
Rights	Copyright is held by the author.
Language	English
Type	Text
Format	application/pdf
Media Type	Manuscripts
Resource Identifier	mtd1989_udo_dg
Abstract	Analytical procedures were developed, on HPLC, for the separation and quantitation of the methyl, ethyl, propyl and butyl ethers of p-N,N-bis(2-chloroethyl)aminophenol (parent compounds: MPM, EPM, PPM, and BPM, respectively), and their selected in vivo metabolites and of the ethyl, propyl and butyl ethers of 4-N,N-bis(2-chloroethyl)amino-o-cresol (parent compounds: ECM, PCM and BCM, respectively), and their selected in vivo metabolites. For each parent compound and its selected in vivo metabolites, in plasma, the procedure was validated for linearity, system precision, method precision, accuracy (recovery), limit of detection (sensitivity), limit of quantitation, selectivity, and stability. The development and validation of the analytical procedures are discussed. The parent compounds were administered i.v. to male Long-Evans rats and plasma from blood samples collected at appropriate intervals was analyzed on HPLC. The plasma concentration of PCM was statistically significantly higher than those of the other compounds. There was no specific relationship between plasma concentration and alkyl chain length or type of compound (phenolic or cresol). Each parent compound exhibited monophasic disappearance from the plasma with mean elimination half-lives ranging from 12 min for EPM to 63.62 min for PPM. There were statistically significant differences among the pharmacokinetic parameters of some of the parent compounds but there was no specific relationship between any pharmacokinetic parameter and alkyl chain length or type of compound. The relationship between selected pharmacokinetic parameters and plasma concentration and the interrelationship of the pharmacokinetic parameters are discussed. Multiple metabolic pathways were observed for each parent compound. For the parent phenolic compounds, O-dealkylation is one of the pathways. The extent of O-dealkylation was greater for the shorter chain compounds. O-dealkylation could not be established for the parent cresol compounds because of inability to recover 4-N,N-bis(2-hydroxyethyl)amino-o-cresol from the plasma, in vitro, at concentrations useful for the studies. Therefore, the effect of steric hinderance (by the 2-methyl group) on the O-dealkylation of the cresol compounds could not be established.

Comparative studies on selected alkyl ethers of p-N,N-bis (2- chloroethyl) aminophenol and of 4-N,N-bis (2-chloroethyl) amino-o-cresol : pharmacokinetic parameters and metabolic profiles

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