Pharmacokinetics of Cimetidine after Single Doses and during Continuous Treatment

Abstract

The plasma concentration-time curve and urinary excretion of cimetidine were followed in 10 patients after single 200mg doses given intravenously, in 9 patients after 400 and 800mg single oral doses, and in 10 patients over a 24-hour period during continuous oral treatment with 1000mg daily.

The bioavailability of cimetidine measured as the ratio between the areas under the plasma concentration-time curves (AUC) after oral and intravenous administration was 76%. The mean excretion of cimetidine in the urine as unchanged drug, expressed as a percentage of administered dose, was 58% after 200mg intravenously and between 37 and 41% after single oral doses of 200, 400 and 800mg and during continuous treatment with 1.0g/day. Since there were no significant differences between the oral doses, the relative bioavailability of cimetidine does not appear to be dose-dependent.

The AUC after the 800mg dose was 2.1 times that of the 400mg dose. No dose-dependent kinetics were observed. There were also no significant differences in the AUCs after 200 and 400mg doses during continuous treatment compared with the AUCs after the same single doses. Thus, cimetidine does not appear to induce or inhibit its own metabolism during treatment.

Following intravenous administration, the mean volume of distribution was 1.39L/kg and the mean total body clearance and the mean plasma renal clearance of cimetidine were 655 and 375ml/min, respectively. A renal clearance of cimetidine more than 3 limes higher than the creatinine clearance demonstrates that the renal excretion of cimetidine is mainly by tubular secretion.

Plasma concentrations of cimetidine during continuous treatment with 1.0g/day were above 1.0μg/ml — the plasma concentration associated with 50% inhibition of stimulated acid secretion in peptic ulcer patients — for 9 out of the 24 hours. A morning plasma concentration above 0.6μg/ml before the next morning dose has been taken during treatment with cimetidine 1.0g/day is only seen in patients with some degree of renal failure.

Measurement of plasma half-life during continuous treatment shows that the plasma half-life is longer than the mean 1.79 hours estimated after intravenous administration of a single dose.