Pharmacokinetic and pharmacodynamic properties of histamine H2-receptor antagonists. Relationship between intrinsic potency and effective plasma concentrations

Histamine H2-receptor antagonists are a unique class of compounds. Pharmacologically they are characterised as a family by their ability to inhibit the secretion of gastric acid, and kinetically they are classified as a family by their similarity in absorption, distribution and elimination. All the H2-receptor antagonists exhibit classical competitive drug-receptor interactions, with Schild slope parameters not significantly different from unity. Comparison of the values of the negative logarithm of the molar concentration of antagonist in the presence of which the potency of the agonist is reduced 2-fold (PA2) indicates that famotidine is about 20 to 50 times more potent than cimetidine and 6 to 10 times more potent than ranitidine. To date, famotidine is the most potent among marketed H2-receptor antagonists. Oral absorption of all the H2-receptor antagonists under clinical investigation is fairly rapid. Peak plasma concentrations are usually attained within 1 to 3h after the dose, but a second peak after oral administration has been observed with cimetidine, ranitidine, famotidine, ramixotidine and etintidine. The mean oral bioavailability for the H2-antagonists ranges from 50 to 70%. Reports on the plasma profiles after intravenous administration are available only for cimetidine, ranitidine, famotidine and nizatidine: plasma concentrations of all 4 decline in a biexponential manner. All of the H2-antagonists are eliminated quite rapidly, with a terminal half-life of 1 to 3h and a total body clearance of 24 to 48 L/h. Elimination is mainly attributable to renal excretion, with renal clearances ranging from 13.8 to 30 L/h. As the values for renal clearance greatly exceed the glomerular filtration rate (6 to 7.2 L/h), it is apparent that renal tubular secretion plays an important role. There is a simple, direct correlation between plasma concentrations of H2-receptor antagonists and the inhibition of gastric acid secretion. This implies a rapid equilibration between drug concentration in plasma and at the site of action, and a reversible drug-receptor interaction. Success in correlating the plasma concentration of H2-receptor antagonists and their pharmacological effects stems from reliable and precise measurement of both items. Despite the heterogeneous nature of data sources, 50% inhibitory concentration (IC50) values for cimetidine, ranitidine, famotidine, nizatidine, etintidine and roxatidine obtained in vitro appear to be in good agreement with those determined in vivo. These results suggest that at an early stage of development of an H2-receptor antagonist, IC50 determined from in vitro studies may be useful as a first approximation to predict the clinically effective concentration of the new agent.