Identification and quantitative determination of glutathione-related urinary metabolites of fotemustine, a new anti-cancer agent.
1. Potential sulphur-containing metabolites of the anticancer agent, fotemustine, were synthesized, namely thiodiacetic acid (TDA), S-2-hydroxyethyl N-acetyl-L-cysteine (2-HE-NAC), N-acetyl-L-cysteine (NAC), S-methyl N-acetyl-L-cysteine (M-NAC), S-carboxymethyl-L-cysteine (CM-Cys), S-carboxymethyl N-acetyl-L-cysteine (CM-NAC), their corresponding sulphoxides and sulphones. Their chemical structures and stabilities were confirmed and derivatization methods were developed for their analysis by sulphur-selective g.l.c. (g.l.c.-FPD) and g.l.c.-mass spectrometry. 2. Four methods for isolation of potential metabolites of fotemustine were developed. Quantification of metabolites, derived in various ways was carried out by g.l.c.-atomic emission detection (AED) or g.l.c.-mass spectrometry. 3. Male Wistar rats (n = 4) were given a single i.p. dose of 40 mg/kg fotemustine. Urine excretion of TDA (18.4 +/- 1.9% in 24 h) and TDA sulphoxide (12.0 +/- 1.6% in 24 h) was significant; 32.7 +/- 4.6% of the fotemustine dose was excreted as TDA, and TDA sulphoxide in 48 h. NAC was excreted in rat urine at 1% of the dose. No other potential glutathione-derived metabolites of fotemustine were excreted. 4. Male Wistar rats (n = 4) were also treated i.p. with fotemustine at 5, 20 and 40 mg/kg, to investigate dose dependency and the time course of excretion of TDA. Excretion of TDA in 48 h urine decreased from 32 +/- 2 to 17 +/- 2% dose (mean +/- SD) with increasing dose of fotemustine.
Brakenhoff
J P
JP
Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands.
Commandeur
J N
JN
Lamorée
M H
MH
Dubelaar
A C
AC
van Baar
B L
BL
Lucas
C
C
Vermeulen
N P
NP
D000818:Animals; D000970:Antineoplastic Agents / Q000652:urine*; D002849:Chromatography, Gas; D005612:Freeze Drying; D008401:Gas Chromatography-Mass Spectrometry; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D009607:Nitrosourea Compounds / Q000652:urine*; D009943:Organophosphorus Compounds / Q000652:urine*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D012997:Solvents; D005978:Glutathione; C054368:fotemustine