Role of thiocyanate ion in detoxification of the anticancer agent chlorambucil.
N,N-Bis(2-chloroethyl)-p-aminophenylbutyric acid (chlorambucil, 1) is an orally administrated drug widely used in the chemotherapy of chronic lymphocytic leukemia. We have recently described a new metabolic path for the decomposition of 1 in human gastric juice based on its reactions with saliva-derived thiocyanate ion. We report here our quantitative data on the reactions of thiocyanate ion with CLB in various fluid matrixes at 37 degreesC. The rate of decomposition of 1 is zero-order with respect to SCN- concentration up to 100 mM. However, thiocyanate ion reacts ca. 18 300 times faster than water with the aziridinium ion derived from 1 at neutral and acidic pH. When the SCN- concentration was greater than 10 mM, practically no N,N-bis(2-hydroxyethyl)-p-aminophenylbutyric acid, 4, the product of chlorambucil hydrolysis, could be detected. Thiocyanate ion also effectively overcompensates for the rate retardation caused by Cl-; 10 mM SCN- is enough to decrease the effect of 0.5 M chloride ion to one-half. This is an important factor in human gastric juice where the chloride ion concentration is normally high.
Hovinen
J
J
Wallac Oy, P.O. Box 10, FIN-20101 Turku, Finland. jari.hovinen@wallac.fi
Pettersson-Fernholm
T
T
Lahti
M
M
Vilpo
J
J
D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics*; D002699:Chlorambucil / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D006207:Half-Life; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008658:Inactivation, Metabolic; D007700:Kinetics; D013056:Spectrophotometry, Ultraviolet; D013861:Thiocyanates / Q000378:metabolism*
D018906:Antineoplastic Agents, Alkylating; D013861:Thiocyanates; D002699:Chlorambucil