AMLODIPINE DYNAMIC EFFECTS AND MYOCARDIAL PHARMACOKINETICS IN THE ISOLATED AND PERFUSED GUINEA-PIG HEART

Myocardial dynamic effects and pharmacokinetics of amlodipine were stu died in the isolated retrogradely perfused and spontaneously beating g uinea-pig heart. Pharmacokinetic analysis of drug accumulation showed one-compartment characteristics with an half-life of 76 min, whereas d isposition exhibited two-compartment characteristics with phasic half- lives of 25 and 174 min., respectively. Myocardial drug accumulation w as increased by 600 times at steady-state compared to the perfusion li quid. Dynamic effect parameters were studied during increasing amlodip ine concentrations from 0.16 to 220 nM. Dynamic steady-states develope d within 20 min. Coronary flow-rate increased with an E-max of 119% an d an EC50 of 1.2 10(-8) M. Amlodipine produced inhibitory effects on c ontraction amplitude and velocities of contraction and relaxation. Obs erved E-max-values and curve-fitted EC50-values were: 97, 97 and 94% a nd 1 . 10(-8) 7.7 . 10(-9) and 2.1 . 10(-8) M. respectively Heart freq uency was not changed. Oxygen consumption increased markedly to a maxi mum of 44% at 3 . 10(-8) M amlodipine and then decreased to nearly ini tial values. The frequency-corrected QT-interval decreased to a maxima l extent of 20% at the three highest concentrations. Myocardial effici ency expressed as the ratio of contraction velocity times frequency to oxygen consumption exhibited a progressive decline to about 2% of ini tial values. The PQ-interval was not changed and the QRS-interval show ed only a small but significant decrease at the highest amlodipine con centration. No arrythmogenic effects were observed. The study demonstr ated a very slow accumulation and disposition of amlodipine in the gui nea-pig heart with a steady-state myocardial drug concentrating accumu lation of 600 times. Marked increase in coronary how-rate and oxygen c onsumption accompanied by a progressive negative inotropic effect were observed.