Clinical Pharmacokinetics

, Volume 8, Issue 6, pp 463–495 | Cite as

Clinical Pharmacokinetics of Cimetidine

  • Andrew Somogyi
  • Roland Gugler
Review Article


Cimetidine is the first histamine H2-receptor antagonist with wide clinical application. It is a weak base and a highly water-soluble compound which can be measured in biological fluids by a number of high-pressure liquid Chromatographic methods.

Following intravenous administration, the plasma concentration profile follows multicompartmental characteristics. The total systemic clearance is high (500 to 600 ml/min) and is mainly determined by renal clearance. The volume of distribution (Vdβ or Vdss) is of the order of 1 L/kg and this about equals bodyweight. Elimination half-life is approximately 2 hours.

Following oral administration of cimetidine, 2 plasma concentration peaks are frequently observed, probably due to discontinuous absorption in the intestine. The absolute bioavailability in healthy subjects is about 60%. In patients with peptic ulcer disease, bioavailability is around 70%, but the variation is much greater than in healthy subjects. Absorption and clearance of cimetidine are linear after 200 and 800mg doses. Mean steady-state plasma concentrations on a standard 1000mg daily dose are 1.0 μg/ml (range 0.64–1.64 μg/ml) and are reproducible after treatment periods of up to 2 years. When taken with food, the extent of absorption is unaltered, but a delay occurs and only 1 peak in the plasma concentration curve is apparent. Partial gastrectomy (Billroth I, II) causes an increase in systemic availability of cimetidine by an unclear mechanism.

Distribution of cimetidine leads to extensive uptake into kidney, lung and muscle tissues. It distributes into the cerebrospinal fluid (CSF) at a ratio of 0.1 to 0.2 compared with plasma. The mean saliva to plasma ratio is 0.2 (range 0.1–0.55). Plasma protein binding is 20%, and there is no relevant effect of changes in binding on the pharmacokinetics of cimetidine. Uptake of cimetidine into red blood cells leads to concentrations equal to those in plasma.

Between 50 and 80% of the dose administered intravenously is recovered in urine as unchanged cimetidine. This fraction is less after oral doses, but is independent of the amount of the dose. In ulcer patients, 40% is recovered unchanged in urine after oral administration. Biliary excretion of cimetidine accounts for only 2% of the dose. Metabolites of cimetidine in man represent 25 to 40% of the total elimination, with 1 major metabolite (cimetidine sulphoxide; 10–15%) and 1 minor metabolite (hydroxymethyl cimetidine; 4%). Elimination of cimetidine is accelerated by an average of 15% in the presence of phenobarbitone, due to induction of its metabolism.

The clearance of cimetidine is increased in children, due to increased renal elimination mechanisms. With increasing age, the volume of distribution of cimetidine decreases, total plasma clearance decreases as a function of decreasing renal clearance, plasma half-life increases, and the duration of effective plasma concentrations (above 0.5 μg/ml) increases as well.

In patients with advanced renal insufficiency, total plasma clearance is reduced from a mean of 500 ml/min to less than 200 ml/min, mainly due to a decrease in renal clearance to 50 ml/min or less. Elimination half-life increases from 2 to 4–5 hours in renal failure patients. The absolute bioavailability in renal failure patients is unchanged or slightly higher compared with controls. A dose reduction for cimetidine is suggested according to the degree of renal impairment, with 400mg daily being recommended in patients with minimal renal function. Cimetidine is dialysable during haemodialysis, but less than 20% of the dose is removed after a single dose, and dose adjustment is seldom necessary.

In patients with severe liver cirrhosis, the non-renal clearance of cimetidine is significantly reduced, but bioavailability as well as the duration of effective plasma concentrations (above 0.5 μg/ml) is increased. A dramatic reduction of total plasma clearance and a prolongation of half-life up to 10 times normal may occur when renal failure is associated with chronic liver disease. In intensive care patients, the dosage of cimetidine frequently has to be increased to 1800mg daily to achieve sufficient elevation of gastric pH, and plasma concentrations above 1.5 μg/ml are required in most patients. The mean elimination half-life in these patients is 2.7 hours, but a wide variation in all parameters is observed.

Cimetidine crosses the placenta and is detectable in the fetus in considerable concentrations. It also is secreted into breast milk of nursing mothers and may reach the infant in amounts of several milligrams daily.

Cimetidine concentrations between 0.5 and 1.0 μg/ml are required to suppress gastric acid secretion under basal conditions or stimulated by pentagastrin or food. Attempts to correlate plasma concentrations of cimetidine or any of the pharmacodynamic parameters to duodenal ulcer healing have so far failed, and thus prediction of therapeutic response from pharmacokinetic data appears disappointing. In cases of overdosage with cimetidine, the pharmacokinetics are unchanged, even with plasma concentrations above 30 μg/ml. Central nervous system side effects such as mental confusion develop in elderly patients and in patients with severe renal or hepatic impairment. In such cases concentrations of cimetidine in the CSF are elevated due to high plasma concentrations and due to a more permeable blood/brain barrier in patients with liver disease.


Clinical Pharmacology Cimetidine Duodenal Ulcer Renal Clearance Clinical Pharmacokinetic 
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Copyright information

© ADIS Press Australasia Pty Ltd. 1983

Authors and Affiliations

  • Andrew Somogyi
    • 1
  • Roland Gugler
    • 1
  1. 1.Department of Clinical and Experimental PharmacologyUniversity of AdelaideAustralia

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