Receptor binding of propranolol is the missing link between plasma concentration kinetics and the effect-time course in man

Abstract

In a double-blind, placebo-controlled study in 6 healthy volunteers, the correlation between beta-adrenoceptor binding, the time course of the effect and plasma concentration kinetics was investigated from 0 to 48 h after a single oral dose of propranolol 240 mg. First, the in vitro beta-adrenoceptor interaction of propranolol was investigated. Propranolol inhibited beta-adrenoceptor binding to rat parotid (beta 1) and reticulocyte (beta 2) membranes in the presence of pooled human plasma with a Ki of about 8 ng/ml plasma. After oral administration of 240 mg propranolol, concentration kinetics in plasma could be described by a Bateman function with a fictive concentration at time 0 of 275 ng/ml plasma, and a mean elimination half-life of 3.5 h. Using the concentration kinetics of propranolol in plasma together with its in vitro beta-adrenoceptor binding characteristics in the presence of placebo plasma from each individual, the time course of antagonism against beta-adrenoceptor mediated effects was predicted. The latter was in agreement with the time course of propranolol-induced inhibition of tachycardia due to orthostasis. After bicycle ergometry, however, the time course of inhibition of tachycardia was shorter than was predicted. Plasma sampled at various times after propranolol administration inhibited beta-adrenoceptor binding of the radioligand 3H-CGP 12177 to rat reticulocyte membranes in a fashion reflecting the time course of inhibition of exercise tachycardia observed in the volunteers. A direct, linear relation was shown between the in vitro inhibition of beta-adrenoceptor binding by the plasma samples withdrawn after propranolol administration and the inhibition of exercise tachycardia observed in parallel. The results show that the concentrations of antagonist present in plasma are representative of the concentrations in the effect compartment. Deep compartments of drug distribution appear irrelevant to the effects of the drugs. The relation between the plasma concentration of propranolol and the reduction in heart rate at various levels of physical effort shows no significant inhibition at rest and increasing IC50-values from orthostasis to 2 min and to 4 min of ergometry. IC50-values after orthostasis are in the range of the Ki-values from in vitro receptor binding studies, whereas the IC50-values after exercise are shifted 2- to 3-fold to the right relative to the Ki-values. This finding is in agreement with increased beta-adrenoceptor stimulation with increasing effort (release of endogenous noradrenaline), which shifts the antagonist concentration-effect curve to the right.(ABSTRACT TRUNCATED AT 400 WORDS)

Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose‐effect curves and baroreceptor reflex.

“…The underlying pharmacological principles and mathematical transformation of the data have been described previously (Wellstein et al, 1985(Wellstein et al, , 1987bBelz et al, 1987). The dose-ratios minus one (DR-1) were calculated in relation to the first agonist dose-response curve established at 08.00 h baseline on day 7 of the placebo treatment period.…”

A method for estimating the potency of angiotensin‐converting enzyme inhibitors in man.

“…The high potency of cilazapril in man is in accordance with results from in vitro and in vivo animal experiments (Natoff et al, 1985). The apparent K--dose and the drug half-life characteristics (or clearance respectively) determines the dosage required for daily chronic intake (Wellstein et al, 1985). From studies in hypertensives, it was apparent that a single daily dose of 2.5 mg of cilazapril (-4 x Kj) has optimum antihypertensive efficacy (Belz et al, 1986).…”

“…Application of classic pharmacologic methodology (Arunlakshana & Schild, 1959) should allow one to quantitate the competitive antagonism between A-I and ACE inhibitors seen in in vitro studies (Ondetti & Cushman, 1982;Strittmatter & Snyder, 1986 (Arunlakshana & Schild, 1959;Wellstein et al, 1985). The aim of this study was to apply these principles to establish a dose-response relationship for a new ACE inhibitor, cilazapril (Hassall et al, 1982;Natoff et al, 1985 1.25, 3.75, 10, and 30 mg of cilazapril orally with a 7 day washout period between the test days.…”

“…The basic principles and mathematical transformation of data were done as described previously (Wellstein et al, 1985Belz et al, 1987 The left panel of Figure 1 shows the effects of A-I on BPdias under control conditions and 3 h after the various doses of cilazapril. The increase of BPdias induced by A-I during the various control assessments is nearly identical.…”

Clinical Trial Simulation in Drug Development

“…However, it allows computation of the concentration producing a 50% change in the maximum effect, which relates directly to drug potency defined as the ratio between the association and dissociation rate constant between drug and receptor. [14,15] This is true for hyperbolic models used in direct-action as well as indirect-action models. [11,16] In this sense, compartmental as well as E max models lie between descriptive and mechanistic models.…”