Correlations between the pharmacological effects and the pharmacokinetic behaviour of tetraminol.

Tetraminol (trans-2-hydroxyethylamino-3-hydroxy-5,8-dimethoxy-1,2,3, 4-tetrahydronaphthalene hydrochloride) is a newly synthesized antihypotensive agent. Its pressor activity is accompanied by a compensatory slowing down of heart rate. Changes in plasma levels after intravenous administration of 1 and 2 mg/kg b.w. to rats and rabbits can be fitted to a two-compartment open pharmacokinetic model (previous communications). Experiments were carried out with simultaneous registration of effects on blood pressure (R1) and heart rate (R2). Mathematical treatment of data for R1 and R2 revealed that changes with time can be described by biexponential equations of the type: R1i = A1i.e-a1it+B1i..e-a21t. Three different ways to correlate the data from the pharmacological and pharmacokinetic experiments were tried: 1) For the time interval during which the pharmacological response changes in the range Rimax- 20 to Rimax- 80% there exists a linear relationship with a high degree of statistical significance between the changes in the effects and plasma levels. 2) In the lambda 1-phase of the drug distribution there also exists a linear relationship between the effects and plasma levels. This is so because Tetraminol exhibits its pressor effect by direct stimulation of alpha-adrenergic receptors in the walls of the peripheral blood vessels. 3) Most suitable for expressing the relationship which exists between the pharmacological effects and the plasma concentration of Tetraminol for the entire time interval is the nonlinear function of the type: Ri/(Rimax - Ri) = QiCsi.