Clinical Pharmacokinetics of Cimetidine
- 95 Downloads
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.
KeywordsClinical Pharmacology Cimetidine Duodenal Ulcer Renal Clearance Clinical Pharmacokinetic
Unable to display preview. Download preview PDF.
- Bianchi Porro, G.; Lazzaroni, M. and Lodola, E.: Blood levels of cimetidine in patients with liver cirrhosis. International Journal of Clinical Pharmacolog, Therapy and Toxicology 7: 374–377 (1983).Google Scholar
- Bodemar, G.; Norlander, B. and Walan, A.: Blood concentration of cimetidine during long-term treatment; in Creutzfeldt (Ed.) Cimetidine. Proceedings of an International Symposium on Histamine H2-Receptor Antagonists, pp. 229–232 (Excerpta Medic, Amsterdam 1978).Google Scholar
- Bodemar, G.; Norlander, B.; Fransson, L. and Walan, A.: The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine: Studies in patients with peptic ulcer disease. Brit. J. Clin. Pharmacol. 7: 23–31 (1979).CrossRefGoogle Scholar
- Burgess, E.; Cutler, R.E. and Blair, A.D.: Cimetidine pharmacokinetics in hemodialysis patients and inhibition of creatinine secretion in healthy subjects. Clinical Pharmacology and Therapeutics 27: 247 (1980).Google Scholar
- Dupont, T.; Beaugrand, M.; Brunet, J.-M.; Azouz-Abdallah, M.; Baylocq, D.; Champault, G. and Ferner, J.-P.: Plasma concentrations of cimetidine in cirrhotic and noncirrhotic patients with upper digestive tract hemorrhage. Gastroenterologie Clinique et Biologique 5: 155–160 (1981).PubMedGoogle Scholar
- Gibson, T.P.: Influence of renal disease on pharmacokinetics; in Evans et al. (Eds) Applied Pharmacokinetics: Principles of Therapeutic Drug Monitoring, pp. 32–56 (Applied Therapeutic, San Francisco 1980).Google Scholar
- Griffiths, R.; Lee, R.M. and Taylor, D.C.: Kinetics of cimetidine in man and experimental animals; in Burland and Simkins (Eds) Cimetidine: Proceedings of the Second International Symposium on Histamine H2-Receptor Antagonists, pp. 38–59 (Excerpta Medic, Amsterdam 1977).Google Scholar
- Gugler, R.; Somogyi, A. and von Bergmann, K.: The biliary excretion of histamine H2-receptor antagonists cimetidine and oxmetidine. Clinical Pharmacology and Therapeutics 29: 249–250 (1981b).Google Scholar
- Gugler, R.; Wolf, H.; Kliems, G. and Somogyi, A.: Bioverfügbarkeit von Cimetidin nach Magenteilresektoin. Münchner Medizinische Wochenschrift 122: 1337–1340 (1980).Google Scholar
- Larsson, R.; Erlanson, P.; Bodemar, G.; Walan, A.; Bertler, A.; Fransson, L. and Norlander, B.: The pharmacokinetics of cimetidine and its sulphoxide metabolite in patients with normal and impaired renal function. British Journal of Clinical Pharmacology 13: 163–170 (1982b).PubMedCrossRefGoogle Scholar
- Lorenz, W.; Fischer, M.; Rohde, H.; Troidl, H.; Reimann, H.J. and Ohman, Ch.: Histamine and stress ulcer: New components in organizing a sequential trial on cimetidine prophylaxis in seriously ill patients and definition of a special group at risk (severe polytrauma). Klinische Wochenschrift 58: 653–665 (1980).PubMedCrossRefGoogle Scholar
- Nouel, O.; Bernuau, J.; Lebar, M.; Rueff, B. and Benhamou, J.-P.: Cimetidine-induced mental confusion in patients with cirrhosis. Gastroenterology 79: 780–781 (1980).Google Scholar
- Okolicsanyi, L.; Venuti, M.; Orlando, R.; Lirussi, F.; Nassuato, G. and Benvenuti, C.: Oral and intravenous pharmacokinetics of cimetidine in liver cirrhosis. International Journal of Clinical Pharmacolog, Therapy and Toxicology 20: 482–487 (1982).Google Scholar
- Randolph, W.C.; Osborne, V.L. and Intoccia, A.P.: Cimetidine sulphoxide: Whole blood levels in normal human subjects and patients with varying degrees of renal failure. Pharmacologist 22: 278 (1980).Google Scholar
- Rovata, V.; Foschi, D.: Benevenuti, C. and Alfieri, G.: Pharmacokinetics of cimetidine in patients with unresponsive duodenal ulcer. International Journal of Clinical Pharmacology Research 2: 71–76 (1983).Google Scholar
- Rowley-Jones, D. and Grainger: Cimetidine by intramuscular administration: Efficacy and safety. World Conference on Clinical Pharmacology and Therapeutic, London, 1980, Abstract No. 399 (MacMilla, London 1980).Google Scholar
- Rune, S.J.; Hesselfeldt, P. and Larsen, N.-E.: Clinical and pharmacological effectiveness of cimetidine in duodenal ulcer patients. Scandinavian Journal of Gastroenterology 14: 489–492 (1979).Google Scholar
- Rune, S.J.; Larsen, N.-E.; Stadil, F. and Worning, H.: Development of resistance to cimetidine in a patient with Zollinger-Ellison syndrome. Gastroenterology 80: 1265 (1981).Google Scholar
- Sjöqvist, F.; Borgå, O. and Orme, M.L.E.: Fundamentals in clinical pharmacology: in Avery (Ed.) Drug Treatment, 2nd ed., pp. 1–61 (AD1S Pres, Sydney 1980).Google Scholar
- Spence, R.W.; Celestin, L.R.; De la Guardia, R.; MacMullen, C.A. and McCormick, D.A.: Biliary secretion of cimetidine in man; in Burland and Simkins (Eds) Cimetidine: Proceedings of the Second International Symposium on Histamine H2-Receptor Antagonists, pp. 81–84 (Excerpta Medic, Amsterdam 1977).Google Scholar