Drug Interactions with Cimetidine
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Because of widespread (and often uncritical) use of Cimetidine, there is considerable potential for interactions to occur with other drugs.
In studies on absorption, benzylpenicillin absorption was not disturbed by Cimetidine in most cases, but a several-fold increase in urinary excretion occurred repeatedly in I subject, indicating that increased absorption of acid-labile compounds may occur in some patients. The absorption of ketoconazole was reduced by more than half with Cimetidine, a consequence of its poor water solubility which is enhanced in acid solution. Conflicting results are reported with tetracycline, the overall absorption of which does not appear to be significantly altered by Cimetidine. Aspirin absorption was halved by Cimetidine in 3 of 6 subjects, when the intragastric pH was raised above 3.5. Cimetidine did not affect the absorption of ampicillin, co-trimoxazole or prednisolone.
Cimetidine has been shown to inhibit various microsomal drug-metabolising enzymes in animal as well as human liver, most likely through the binding of the imidazole ring structure of Cimetidine to the haeme moiety of cytochrome P-450. In 7 studies, Cimetidine uniformly prolonged antipyrine half-life by 18 to 37% and reduced its clearance by 10 to 27%. After chronic dosing with Cimetidine, warfarin clearance was reduced from 3.4 to 2.5ml/min, whilst the volume of distribution and elimination half-life remained unchanged. Steady-state warfarin concentrations, as well as Prothrombin times, increased upon addition of Cimetidine to the treatment regimen. Warfarin concentration and effect both returned to pre-Cimetidine values when Cimetidine was withdrawn. Amongst the benzodiazepines, diazepam, desmethyldiazepam and chlordiazepoxide plasma clearance values were reduced by Cimetidine by 43, 28 and 63 %, respectively, and half-lives increased accordingly, while volumes of distribution and protein binding were not affected. Long term treatment with Cimetidine and diazepam resulted in a 30 to 80% increase in steady-state diazepam concentrations. In contrast, the pharmacokinetics of oxazepam and lorazepam, which are eliminated almost entirely by glucuronidation and not oxidation, were not altered by Cimetidine. Cimetidine also inhibits the metabolism of phenytoin, theophylline and carbamazepine.
A single dose of Cimetidine decreased indocyanine green clearance by 23%, which was interpreted as a reduction in hepatic blood flow. The area below the Propranolol concentration-time curve (oral administration) was increased by between 25 and 60 % with Cimetidine and by 25 % after intravenous administration of Propranolol, with no change in elimination half-life, volume of distribution or bioavailability. With chronic oral Propranolol dosing, Cimetidine increased the steady-state concentration from 23.2 to 44.9ng/ml. The bioavailability of labetalol almost doubled from 30 to 54 % with Cimetidine, with no change in half-life and systemic clearance. The oral clearance and elimination half-life of chlormethiazole was increased by 30 and 50%, respectively, by Cimetidine. Studies with high hepatic clearance drugs have not consistently shown cimetidine-induced changes in systemic clearance (liver blood flow dependent), but oral clearance increased in all cases, consistent with inhibition of drug metabolism.
Peculiarities of Cimetidine effect on drug metabolism are (a) only about 20% of a Cimetidine dose is metabolised in man, as compared with a much larger fraction with other inhibitory drugs; (b) the maximum effect attained occurs within I day whereas offset of effect varies with individual interacting drugs; (c) the degree of inhibition of metabolism is much more pronounced in patients with already impaired liver function (i.e. liver disease).
Antacids of a weak neutralising capacity (10 to 15mmol/dose) did not influence the absorption of Cimetidine. However, antacids (aluminium plus magnesium hydroxide) with a neutralising capacity between 26 and 41 mmol/10ml reduced the bioavailability of Cimetidine by 20 to 35%. A recent study with an aluminium plus magnesium hydroxide antacid of 70mmol/10ml did not affect Cimetidine bioavailability. The antacid preparation used differed from others by a disproportionate increase in the aluminium hydroxide content. Metoclopramide and propantheline also reduced the absorption of Cimetidine by an average of 20 %, indicating the importance of gastric emptying for Cimetidine absorption. Phenobarbitone administration over 3 weeks led to an increase in Cimetidine plasma clearance by 18%, mainly due to an increase in the non-renal clearance, but probably also partially due to a reduction in Cimetidine absorption.
The most important clinical consequences of interactions with Cimetidine primarily involve inhibition of drug metabolism. Clinically important interactions are predominantly manifested in those drugs which have a narrow therapeutic index (e.g. Phenytoin, warfarin, theophylline). The interaction leads to higher steady-state blood concentrations and hence increases the incidence of side effects and toxicity. Adverse effects of such interactions can be avoided by careful monitoring and adjustment of dosage for those drugs which undergo phase I metabolic detoxification in the liver when it is necessary to administer such drugs concomitantly with Cimetidine.
- Ambrose, P.J. and Harralson, A.F.: Lack of effect of Cimetidine on theophylline clearance. Drug Intelligence and Clinical Pharmacy 15: 389–390 (1981).
- Bank, S.; Saunders, S.J.; Marks, I.N.; Novis, B.H. and Barbezat, G.O.: Gastrointestinal and hepatic diseases; in Avery (Ed) Drug Treatment. Principles and Practice of Clinical Pharmacology and Therapeutics, 2nd ed., pp.683–759 (ADIS Press, Sydney 1980).
- Barr, W.H.; Adir, J. and Garrettson, L.: Decrease of tetracycline absorption in man by sodium bicarbonate. Clinical Pharmacology and Therapeutics 12: 779–784 (1971).
- Bianchi Porro, G.; Burland, W.L.; Hawkins, B.W. and Petrillo, M.: Long-term treatment of duodenal ulcer with Cimetidine: A review; in Torsoli et al. (Eds) Further Experience with H3-Receptor Antagonists in Peptic Ulcer Disease and Progress in Histamine Research, pp.91–98 (Excerpta Medica, Amsterdam 1980).
- 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. Br. J. Clin. Pharmacol. 7: 23–31 (1979a). CrossRef
- Bodemar, G.; Norlander, B. and Walan, A.: Diminished absorption of Cimetidine caused by antacids. Lancet 1: 444–445 (1979b). CrossRef
- Bodemar, G.; Gotthard, R.; Ström, M.; Walan, A.; Jönsson, B. and Bjarulf, P.: Socioeconomic aspects of treatment with Cimetidine in peptic ulcer disease; in Torsoli et al. (Eds) Further Experience with H2-Receptor Antagonists in Peptic Ulcer Disease and Progress in Histamine Research, pp.59–67 (Excerpta Medica, Amsterdam 1980).
- Brogden, R.N., Heel, R.C., Speight, T.M. and Avery, G.S.: Cimetidine: A review of its pharmacological properties and therapeutic efficacy in peptic ulcer disease. Drugs 15: 93–131 (1978). CrossRef
- Burland, W.L.; Darkin, D.W. and Mills, M.W.: Effect of antacids on absorption of Cimetidine. Lancet 2: 965 (1976). CrossRef
- Calandre, E.P.; Calvin, J.G.; Alférez, N.P. and Sanchéz, M.C.F.: Cimetidine-phenytoin interaction. European Journal of Clinical Pharmacology. In press (1981).
- Charbon, G.A.; Brouwers, H.A.A. and Sala, A.: Histamine H1-and H2-receptors in the gastrointestinal circulation. Naunyn-Schmiedeberg’s Archives of Pharmacology 312: 123–129 (1980). CrossRef
- Cole, J.J.; Charles, B.G. and Ravenscroft, P.J.: Interaction of Cimetidine with tetracycline absorption. Lancet 2: 536 (1980). CrossRef
- Daneshmend, T.K. and Roberts, C.J.C.: Cimetidine and bioavailability of labatolol. Lancet 1: 565 (1981). CrossRef
- Daneshmend, T.K.; Ford, J. and Roberts, C.J.C.: Variability in the enzyme inhibiting effect of Cimetidine in man. British Journal of Clinical Pharmacology 10: 421P (1980).
- Desmond, P.V.; Patwardhan, R.V.; Schenker, S. and Speeg, K.V.: Cimetidine impairs elimination of chlordiazepoxide (Librium) in man. Annals of Internal Medicine 93: 266–268 (1980).
- Desmond, P.V.; Shaw, R.G.; Bury, R.W.; Mashford, M.L. and Breen, K.J.: Cimetidine impairs the clearance of an orally administered high clearance drug, chlormethiazole. Gastroenterology 80: 1330 (1981).
- Devanesen, S.: Prolongation of Prothrombin time with Cimetidine. Medical Journal of Australia 1: 537 (1981).
- Donovan, M.A.; Heagerty, A.M.; Patel, L.; Castleden, M. and Pohl, J.E.F.: Cimetidine and bioavailability of Propranolol. Lancet 1: 164 (1981). CrossRef
- Dubb, J.W.; Stote, R.M.; Familiar, R.G.; Lee, K. and Alexander, F.: Effect of Cimetidine on renal function in normal man. Clinical Pharmacology and Therapeutics 24: 76–83 (1978).
- Duncan, W.A.M. and Parsons, M.E.: Reminiscences of the development of Cimetidine. Gastroenterology 78: 620–625 (1980).
- Fairfax, A.J.; Adam, J. and Pagan, K.S.: Effect of Cimetidine on absorption of oral benzylpenicillin. British Medical Journal 1: 820 (1978). CrossRef
- Feely, J.; Wilkinson, G.R. and Wood, A.J.J.: Reduction of liver blood flow and Propranolol metabolism by Cimetidine. New England Journal of Medicine 304: 692–695 (1981). CrossRef
- Fine, A. and Churchill, D.N.: Potentially lethal interaction of Cimetidine and morphine. Canadian Medical Association Journal 124: 1434–1436 (1981).
- Finkelstein, W. and Isselbacher, K.J.: Drug therapy: Cimetidine. New England Journal of Medicine 299: 992–996 (1978). CrossRef
- Fisher, P.; House, F.; Inns, P.; Morrison, P.J.; Rogers, H.J. and Bradbrook, I.D.: Effect of Cimetidine on the absorption of orally administered tetracycline. British Journal of Clinical Pharmacology 9: 153–158 (1980). CrossRef
- Fordtran, J.S.; Morawski, S.G. and Richardson, C.T.: In vivo and in vitro evaluation of liquid antacids. New England Journal of Medicine 288: 923–928 (1973). CrossRef
- Garty, M. and Hurwitz, A.: Effect of Cimetidine and antacids on gastrointestinal absorption of tetracycline. Clinical Pharmacology and Therapeutics 28: 203–207 (1980). CrossRef
- Gugler, R.; Fuchs, G.; Diekmann, M. and Somogyi, A.: Plasma concentration response relationship for Cimetidine. Clinical Pharmacology and Therapeutics 29: 744–748 (1981a). CrossRef
- Gugler, R.; Brand, M. and Somogyi, A.: Impaired Cimetidine absorption by antacids and metoclopramide. European Journal of Clinical Pharmacology 20: 225–228 (1981b). CrossRef
- Heagerty, A.M.; Donovan, M.A.; Castleden, C.M.; Pohl, J.F.; Patel, L. and Hedges, A.: Influence of Cimetidine on pharmacokinetics of Propranolol. British Medical Journal 282: 1917–1919 (1981). CrossRef
- Henry, D.A.; Macdonald, I.A.; Kitchingman, G.; Bell, G.D. and Langman, M.J.S.: Cimetidine and ranitidine: Comparison of effects on hepatic drug metabolism. British Medical Journal 281: 775–777 (1980). CrossRef
- Hetzel, D.; Birkett, D. and Miners, J.: Cimetidine interaction with warfarin. Lancet 2: 639 (1979). CrossRef
- Hetzel, D.J.; Bochner, F.; Hallpike, J.F. and Shearman, D.J.C.: Cimetidine interaction with Phenytoin. British Medical Journal 282: 1512 (1981). CrossRef
- Jackson, J.E.: Reduction of liver blood flow by Cimetidine. New England Journal of Medicine 305: 99–100 (1981).
- Jackson, J.E.; Powell, J.R.; Wandell, M.; Bentley, J. and Dorr, R.: Cimetidine-theophylline interaction. Pharmacologist 22: 231 (1980).
- Kanto, J.; Allonen, H.; Jalonen, H. and Mäntylä, R.: The effect of metoclopramide and propantheline on the gastrointestinal absorption of Cimetidine. British Journal of Clinical Pharmacology 11: 527–530 (1981). CrossRef
- Kaplan, S.A.: Biopharmaceutics in the preformulation stages of drug development; in Swarbrick (Ed) Current Concepts in the Pharmaceutical Sciences: Dosage Form Design and Bioavailability, pp.1–30 (Lea and Febiger, Philadelphia 1973).
- Khoury, W.; Geraci, K.; Askari, A. and Johnson, M.: The effect of Cimetidine on aspirin absorption. Gastroenterology 76: 1169 (1979).
- Klotz, U. and Reimann, I.: Delayed clearance of diazepam due to Cimetidine. New England Journal of Medicine 302: 1012–1014 (1980a). CrossRef
- Klotz, U. and Reimann, I.: Effect of Cimetidine on the clearance of benzodiazepines. New England Journal of Medicine 303: 754 (1980b). CrossRef
- Klotz, U. and Reimann, I.: Influence of Cimetidine on the pharmacokinetics of desmethyldiazepam and oxazepam. European Journal of Clinical Pharmacology 18: 517–520 (1980c). CrossRef
- Kristensen, M.B.: Drug interactions and clinical pharmacokinetics. Clinical Pharmacokinetics 1: 351–372 (1976). CrossRef
- Mayersohn, M.: Physiological factors that modify systemic drug availability and pharmacologic response in clinical practice; in Blanchard et al. (Eds) Principles and Perspectives in Drug Bioavailability, pp.211–273 (Karger, Basel 1979).
- Melander, A.: Influence of food on the bioavailability of drugs. Clinical Pharmacokinetics 3: 337–351 (1978). CrossRef
- Miners, J.O.; Grygiel, J.J.; Drew, R. and Birkett, D.J.: Interaction between Cimetidine and theophylline in smokers and nonsmokers (abstr.). 14th Annual Meeting of the Australasian Society of Clinical and Experimental Pharmacologists, p.61 (1980).
- Morrison, P.J.; Rogers, H.J.; Bradbrook, I.D. and Parsons, C.: Concurrent administration of Cimetidine and enteric-coated prednisolone: Effect on plasma levels of prednisolone. British Journal of Clinical Pharmacology 10: 87–89 (1980). CrossRef
- Patwardhan, R.V.; Yarborough, G.W.; Desmond, P.V.; Johnson, R.F.; Schenker, S. and Speeg, K.V.: Cimetidine spares the glucuronidation of lorazepam and oxazepam. Gastroenterology 79: 912–916 (1980).
- Patwardhan, R.; Johnson, R.; Sinclair, A.; Schenker, S. and Speeg, K.V.: Lack of tolerance and rapid recovery of cimetidine-inhibited chlordiazepoxide (Librium) elimination in man. Gastroenterology 80: 1344 (1981).
- Pawlik, W.; Tague, L.L.; Teppermarm, B.L., Miller, T.A. and Jacobson, E.D.: Histamine H1- and H2-receptor vasodilation of canine intestinal circulation. American Journal of Physiology 233: E219–E224 (1977).
- Pelkonen, O. and Puurunen, J.: The effect of Cimetidine on in vitro and in vivo microsomal drug metabolism in the rat. Biochemical Pharmacology 29: 3075–3080 (1980). CrossRef
- Puurunen, J. and Pelkonen, O.: Cimetidine inhibits microsomal drug metabolism in the rat. European Journal of Pharmacology 55: 335–336 (1979). CrossRef
- Puurunen, J.; Sotaniemi, E. and Pelkonen, O.: Effect of Cimetidine on microsomal drug metabolism in man. European Journal of Clinical Pharmacology 18: 185–187 (1980). CrossRef
- Reimann, I.W.; Klotz, U. and Frölich, J.C.: Cimetidine increases Propranolol steady-state plasma levels in man (abstr). Eighth International Congress of Pharmacology, Tokyo (1981).
- Rendić, V.; Sunjić, V.; Toso, R.; Kajfež, F. and Ruf, H.H.: Interaction of Cimetidine with liver microsomes. Xenobiotica 9: 555–564 (1979). CrossRef
- Roberts, R.K.; Grice, J.; Wood, L.; Petroff, V. and McGuffie, C.: Cimetidine impairs the elimination of theophylline and antipyrine. Gastroenterology 81: 19–21 (1981).
- Rogers, H.J.; James, C.A.; Morrison, P.J. and Bradbrook, I.D.: Effect of Cimetidine on oral absorption of ampicillin and cotrimoxazole. Journal of Antimicrobial Chemotherapy 6: 297–300 (1980). CrossRef
- Röllinghoff, W.; Sticken, R. and Paumgartner, G.: Inhibition of drug metabolism by Cimetidine in man. Dependence on pretreatment microsomal liver function. Gastroenterology 80: 1347 (1981).
- Rowland, M.; Benet, L.Z. and Graham, G.G.: Clearance concepts in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics 1: 123–135 (1973).
- Ruffalo, R.L. and Thompson, J.F.: Effect of Cimetidine on the clearance of benzodiazepines. New England Journal of Medicine 303: 753–754 (1980). CrossRef
- Serlin, M.J.; Sibeon, R.G.; Mossmann, S.; Breckrenridge, A.M.; Williams, J.R.B.; Atwood, J.L. and Willoughby, J.M.T.: Cimetidine: Interaction with oral anticoagulants in man. Lancet 2: 317–319 (1979). CrossRef
- Silver, B.A. and Bell, W.R.: Cimetidine potentiation of the hypoprothrombinemic effect of warfarin. Annals of Internal Medicine 90: 348–349 (1979).
- Somogyi, A.; Rohner, H.G. and Gugler, R.: Pharmacokinetics and bioavailability of Cimetidine in gastric and duodenal ulcer patients. Clinical Pharmacokinetics 5: 84–94 (1980). CrossRef
- Somogyi, A.; Thielscher, S. and Gugler, R.: Influence of phenobarbital treatment on Cimetidine kinetics. European Journal of Clinical Pharmacology (1981).
- Staiger, Ch.; Simon, B.; de Vries, J.; Kather, H. and Walter, E.: Untersuchungen zur Wirkung von Ranitidin auf den Antipyrin-Metabolismus. Zeitschrift für Gastroenterologie 18: 601–604 (1980).
- Staiger, Ch.; Simon, B.; de Vries, J.; Kather, H.; Dammann, H.G. and Walter, E.: Comparative effects of ICI 125,211 and Cimetidine on antipyrine kinetics. British Journal of Clinical Pharmacology 11: 214–215 (1981).
- Steinberg, W.M. and Lewis, J.H.: Mylanta II inhibits the absorption of Cimetidine. Gastroenterology 78: 1269 (1980).
- Sultatos, L.G.; Dvorchik, B.H.; Vesell, E.S.; Shand, D.G. and Branch, RA.: Further observations on relationships between antipyrine half-life, clearance and volume of distribution: An appraisal of alternative kinetic parameters used to assess the elimination of antipyrine. Clinical Pharmacokinetics 5: 263–273 (1980). CrossRef
- Taylor, D.C.; Cresswell, P.R. and Bartlett, D.C.: The metabolism and elimination of Cimetidine, a histamine H2-receptor antagonist, in the rat, dog and man. Drug Metabolism and Disposition 6: 21–30 (1978).
- Telerman-Toppet, N.; Duret, M. and Coers, C.: Cimetidine interaction with carbamazepine. Annals of Internal Medicine 94: 544 (1981).
- van der Meer, J.W.M.; Keuning, J.J.; Scheijgrond, H.W.; Heykants, J.; van Cutsem, J. and Brugmans, J.: The influence of gastric acidity on the bioavailability of ketoconazole. Journal of Antimicrobial Chemotherapy 6: 552–554 (1980). CrossRef
- Vesell, E.S.: The antipyrine test in clinical pharmacology: Conceptions and misconceptions. Clinical Pharmacology and Therapeutics 26: 275–286 (1979).
- Walkenstein, S.S.; Dubb, J.W.; Randolph, W.C.; Westlake, W.J., Stote, R.M. and Intoccia, A.P.: Bioavailability of Cimetidine in man. Gastroenterology 74: 360–365 (1978).
- Wallin, B.A.; Jacknowitz, A. and Raich, P.C.: Cimetidine and effect of warfarin. Annals of Internal Medicine 90: 993 (1979).
- Weinberger, M.M.; Smith, G.; Milavetz, G. and Hendeles, L.: Decreased theophylline clearance due to Cimetidine. New England Journal of Medicine 304: 672 (1981).
- Welling, P.G.: Influence of food and diet on gastrointestinal drug absorption: A review. Journal of Pharmacokinetics and Biopharmaceutics 5: 291–334 (1977).
- Welling, P.G.; Koch, P.A.; Lau, C.C. and Craig, W.A.: Bioavailability of tetracycline and doxycycline in fasted and nonfasted subjects. Antimicrobial Agents and Chemotherapy 11: 462–469 (1977). CrossRef
- Wilkinson, C.F.; Hetnarski, K. and Hicks, L.J.: Substituted imidazoles as inhibitors of microsomal oxidation and insecticide synergists. Pesticide Biochemistry and Physiology 4: 299–312 (1974). CrossRef
- Wilkinson, G.R.: Pharmacokinetics of drug disposition; Hemodynamic considerations. Annual Review of Pharmacology and Toxicology 15: 11–27 (1975). CrossRef
- Wilkinson, G.R. and Shand, D.G.: A physiological approach to hepatic drug clearance. Clinical Pharmacology and Therapeutics 18: 377–390 (1975).
- Wood, L.; Grice, J.; Petroff, V.; McGuffie, C. and Roberts, R.K.: Effect of Cimetidine on the disposition of theophylline. Australian and New Zealand Journal of Medicine 10: 586 (1980).
- Drug Interactions with Cimetidine
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