The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis

Purpose. The anti-ischemic drug trimetazidine (TMZ) acts by a combination o f molecular mechanisms which begin to be understood. Thus, it acts in the m icromolar range to significantly reduce intracellular acidification during ischemia. To search for a possible physicochemical explanation of this phen omenon, we investigated the transfer mechanisms of the various electrical f orms of this dibasic drug. Methods. The transfer characteristics of TMZ were studied by electrochemist ry at the water/1,2-dichloroethane interface. Cyclic voltammetry was used t o measure the formal transfer potentials of singly and doubly protonated fo rms of TMZ (noted TH+ and TH22+, 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 dissoc iation constants in water were deduced to be pK(at)(w) = 4.54 +/- .02 and p K(a2)(w) = 9.14 +/- 0.02. The partition coefficients of TH+ and TH22+ were found to be respectively log P-TH(0')+ = -3.78 +/- 0.16 and log P(TH2)(0')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 establi shed in the form of its ionic partition diagram, which showed that the affi nity of the ions for the organic phase is pH-dependent and strongly increas ed by the interfacial potential. Conclusions. This behavior suggests a physicochemical mechanism whereby eff lux of protonated TMZ out of an acidified cell is facilitated, in effect ex porting protons to extracellular space.