COMPARATIVE LIPOPHILICITY OF TRANDOLAPRIL AND OTHER ACE-INHIBITORS

Tile lipophilicity of angiotensin converting enzyme inhibitors (ACE-I) available in France has been compared using true complementary method s. Studies have been performed both on active ACE-I and pro drugs. The first study used reverse phase high performance liquid chromatography (HPLC) in order to measure the n-octanol water partition coefficients . They were measured at 3 pH values (2.5, 4.7 and 7.4). The second stu dy was performed on the basis of computer drawn chemical formula. The lipophilic area to hydrophilic area ratio was calculated from the thre e dimensional structure of each ACE-I. A calculated n-octanol water pa rtition coefficient was then determined. Whatever the method, a broad range of values was seen. The HPLC n-octanol water partition coefficie nt ranged from -1.86 (captopril) to 1.02 (trandolaprilate). The lipoph ilic to hydrophilic ratio ranged from 1.33 (captopril) to 2.74 (trando laprilate) and the computer determined n-octanol water partition coeff icient ranged from -0.36 (perindoprilate) to 0.69 (quinaprilate). A st rong correlation (r = 0.971 p = 0.0001) was found between the lipophil ic/hydrophilic area ratio and the HPLC partition coefficient. The clas sification of the ACE-I was very close whatever the mode of determinat ion. The less lipophilic ACE-I are lisinopril and captopril and the mo st lipophilic are quinalapril and trandolapril. Clinical consequences of such differences remain unknown.