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Title

The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis
Authors
Reymond, F.
Steyaert, G.
Carrupt, Pierre-Alain
Morin, D.
Tillement, J. P.
Girault, H. H.
Testa, Bernard
Published in Pharmaceutical Research. 1999, vol. 16, no. 5, p. 616-624
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 TH(2)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 TH(2)2+ were found to be respectively log P0'TH+ = -3.78 +/- 0.16 and log P0'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 physicochemical mechanism whereby efflux of protonated TMZ out of an acidified cell is facilitated, in effect exporting protons to extracellular space.
Keywords Acid-Base Equilibrium/drug effects — Acidosis/*drug therapy — Chemistry, Physical — Electric Conductivity — Electrochemistry — Hydrogen-Ion Concentration — Ischemia/*drug therapy — Lipids/chemistry — Physicochemical Phenomena — Protons — Solubility — Trimetazidine/chemistry/*pharmacology — Vasodilator Agents/chemistry/*pharmacology — Water/chemistry
Identifiers
PMID: 10350001
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Other version: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10350001
Citation
(ISO format) 		REYMOND, F. et al. The pH-partition profile of the anti-ischemic drug trimetazidine may explain its reduction of intracellular acidosis. In: Pharmaceutical Research, 1999, vol. 16, n° 5, p. 616-624. https://archive-ouverte.unige.ch/unige:10643

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Deposited on : 2010-08-06

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