Effect of basal gastric acid secretion on the pharmacodynamics of ranitidine

Twelve patients with inactive ulcer disease were administered placebo and ranitidine via bolus and continuous intravenous infusions, at doses ranging from 50 every 8 h, to 12.5 mg/h for 24 h. Gastric acid was collected for 20 min each h for 24 h, and ranitidine serum concentrations were measured approximately every 2 h, during each of the six study periods. Cosinor analysis of gastric acid secretion during placebo treatment revealed a significant circadian rhythm in all subjects. Mesor acid output ranged from 1.7 to 11.6 mmol/h (mean 5.6 +/- 2.8 mmol/h) and the amplitude ranged from 0.7 to 6.5 mmol/h (mean 2.8 +/- 1.6 mmol/h). Peak acid output (acrophase) occurred at 10 p.m. +/- 3 h. A pharmacodynamic model, relating ranitidine serum concentration to hourly acid secretion, was derived, which incorporated the circadian change in basal acid output. Data for this fractional response model included basal acid secretion--as determined by time of day, measured acid secretion, and associated serum ranitidine concentration. The 50% inhibitory concentration (IC50) for ranitidine ranged from 10-75 ng/ml, with a mean of 44 ng/ml. The variation in IC50 and in basal acid secretion combined to produce a wide variation in the pharmacodynamic response to ranitidine. The model-predicted serum concentrations, required to maintain acid secretion at 0.1 mmol/h, ranged from 250 to 1550 ng/ml, at the time of peak evening acid secretion. Despite a constant degree of acid inhibition by ranitidine during the day, higher serum concentrations are required during times of peak acid output to maintain adequate suppression of hydrogen ion secretion.