ISSN:
1573-904X
Keywords:
trimetazidine
;
lipophilicity
;
proton transfer
;
ionic partition diagram
;
ITIES
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Purpose. The anti-ischemic drug trimetazidine (TMZ) acts by a combination of molecular mechanisms which begin to be understood. Thus, it acts in the micromolar range to significantly reduce intracellular acidification during ischemia. To search for a possible physicochemical explanation of this phenomenon, we investigated the transfer mechanisms of the various electrical forms of this dibasic drug. Methods. The transfer characteristics of TMZ were studied by electrochemistry at the water/1,2-dichloroethane interface. Cyclic voltammetry was used to measure the formal transfer potentials of singly and doubly protonated forms of TMZ (noted TH+ and TH2 2+, respectively ) as a function of aqueous pH, and the partition coefficient of neutral TMZ (log P T) was measured by two-phase titration. Results. log P T was measured to be 1.04 ± 0.06, and the acid-base dissociation constants in water were deduced to be pK w a1 = 4.54 ± .02 and pK w a2 = 9.14 ± 0.02. The partition coefficients of TH+ and TH2 2+ were found to be respectively log P 0′ TH+ = −3.78 ± 0.16 and log P 0′ TH 2 2+= −9.84 ± 0.30, which agrees well with the charge being delocalized on two nitrogen atoms in TH+. The pH-partition profile of TMZ was then established in the form of its ionic partition diagram, which showed that the affinity of the ions for the organic phase is pH-dependent and strongly increased by the interfacial potential. Conclusions. This behavior suggests a physiochemical mechanism whereby efflux of protonated TMZ out of an acidified cell is facilitated, in effect exporting protons to extracellular space.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1023/A:1018899802836
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