Document Detail

Role of thiocyanate ion in detoxification of the anticancer agent chlorambucil.
MedLine Citation:
PMID:  9815200     Owner:  NLM     Status:  MEDLINE    
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.
J Hovinen; T Pettersson-Fernholm; M Lahti; J Vilpo
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  11     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  1998 Nov 
Date Detail:
Created Date:  1999-01-11     Completed Date:  1999-01-11     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  1377-81     Citation Subset:  IM    
Wallac Oy, P.O. Box 10, FIN-20101 Turku, Finland.
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MeSH Terms
Antineoplastic Agents, Alkylating / pharmacokinetics*
Chlorambucil / pharmacokinetics*
Chromatography, High Pressure Liquid
Hydrogen-Ion Concentration
Metabolic Detoxication, Drug
Spectrophotometry, Ultraviolet
Thiocyanates / metabolism*
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Thiocyanates; 305-03-3/Chlorambucil

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