Absorption Of Cimetidine Research Articles

Cimetidine pharmacokinetics in patients with Zollinger-Ellison syndrome

Although most patients with Zollinger-Ellison syndrome can be effectively treated with histamine H2-receptor antagonists, many patients require large doses of drug to inhibit gastric acid secretion adequately. The purpose of the present study was to compare the pharmacokinetics of a 1200-mg oral dose of cimetidine in 9 patients with Zollinger-Ellison syndrome requiring more than 2.4 g/day of cimetidine with 5 age-matched normal volunteers receiving intravenous pentagastrin infusions. Poor responsiveness to cimetidine in patients with Zollinger-Ellison syndrome has several different causes. The concentration of cimetidine in the blood required to inhibit gastric acid secretion by 50% was markedly increased in 3 of the patients with Zollinger-Ellison syndrome, suggesting parietal cell resistance. One patient showed a substantial decrease in cimetidine absorption and 4 patients had delayed cimetidine absorption. Thus 7 of the 9 patients with Zollinger-Ellison syndrome who required more than 2.4 g/day of cimetidine to inhibit gastric acid secretion had abnormal cimetidine pharmacokinetics.

Antacids Do Not Significantly Lower Cimetidine Absorption

Antacids Do Not Significantly Lower Cimetidine Absorption

Effect of metoclopramide on the absorption of cimetidine in rats.

Metoclopramide was found to increase the absorption rate constant (ka) of cimetidine by the duodenum and jejunum in both ligated and unligated rats. The increase of ka of cimetidine in the ligated rats cannot be interpreted in terms of an increase in the gastric emptying rate, which has been suggested to be the main effect of metoclopramide. The pH values of the stomach, duodenum and jejunum increased following the administration of metoclopramide. Atropine also increased the pH value of the duodenum, but it did not increase the ka of cimetidine. Consequently, the increase of ka of cimetidine, following administration of metoclopramide, was not due to the elevation of intestinal pH. On the other hand, metoclopramide significantly increased the blood flow by about 67.3 and 29.7% at the duodenum and jejunum, respectively, when the intestinal blood flow was measured by the hydrogen clearance method. Atropine had no effect on the intestinal blood flow. Based on these results, it was concluded that the increase of intestinal blood flow may be one of the factors for the increase of ka of cimetidine following the administration of metoclopramide. From the results of multi-line fittings of the plasma concentration data following oral, intraduodenal, intrajejunal and intraileac administrations of cimetidine with metoclopramide treatment, it was suggested that metoclopramide increased the intestinal transit time of subsequently administered drugs, as well as the gastric emptying rate.

Study of the absorption site of cimetidine.

The optimal absorption site of cimetidine was assessed in rats. The ileac pH value (measured by a pH meter with a micro pH combination electrode) was slightly higher than that in other intestinal sites, and the absorption rate constant (ka) following the administration of cimetidine into the ligated ileac loop was larger than that in the ligated duodenal and jejunal loops. It is suggested that the ileum is the optimal absorption site of cimetidine. On administration of cimetidine into the ligated and unligated intestines, the ka values of either the duodenum or the ileum were found to be almost the same between the ligated and unligated cases. However, the ka value of the jejunum in the unligated case was slightly larger than that in the ligated case. Thus, it is suggested that cimetidine is completely absorbed in the duodenum and ileum during its passage through these intestinal sites, but at the jejunum an unabsorbed fraction of cimetidine passes to the ileum, where it is absorbed completely. Based on these results, a pharmacokinetic model for the absorption of cimetidine following oral administration was designed, in which gastric, duodenal, jejunal, and ileac compartments were included separately but enterohepatic circulation was not included, because the biliary excretion of cimetidine following intravenous and oral administrations were generally lower than 2% of the dose. The value of k41 was ca. 4 times larger than that of k45, and the value of k45 could be approximated to zero in the model.

Influence of gastric emptying rate on the absorption of cimetidine in rats

Because of the absorption of many drugs from the intestine, the gastric emptying rate relates to the time of appearance of drug action. In the present study, the effects of water volume taken with the drugs, atropine, and metoclopramide on the absorption properties of cimetidine were investigated in rats. As a result the following facts were clarified ; 1) the absorption rate of cimetidine was significantly influenced by water volume taken with drug, and in this case the absorption rate decreased with decreasing water volume, 2) atropine (which decreases the gastric emptying rate) decreasing absorption rate constant of cimetidine, and 3) metoclopramide (which increases the gastric emptying rate) increasing absorption rate constant of cimetidine, respectively. On the other hand, it was also clarified that the first-pass effect of cimetidine was negligible and the change of water volume taken with drug and coadministration of atropine and metoclopramide did not decrease the extent of bioavailability of cimetidine in comparison with the control. Although it is reported that an antacid decreased the bioavailability of cimetidine, in the present study the effect of the antacid (formulated to the reported manner) on the absorption of cimetidine was not observed.

Drug interactions involving cimetidine--mechanisms, documentation, implications.

In summary, cimetidine is a potent inhibitor of liver microsomal activity, which may also decrease hepatic blood flow. Other effects of the drug include inhibition of gastric secretion and intrinsic toxic properties. These effects, combined with the common use of cimetidine in clinical practice, make the risk of adverse drug interactions a relatively frequent risk in the clinical setting. Although a multitude of interactions with cimetidine has been evaluated, many of these are incompletely described or understood. At the present time, a potentially significant alteration of absorption appears to exist with only ketoconazole, elemental iron, vitamin B12 (long-term therapy), and pancreatic enzyme supplements (increased activity). Significant metabolic inhibition or decreased excretion appears to exist with warfarin, propranolol, theophylline, phenytoin, quinidine, possibly lidocaine and procainamide, and certain benzodiazepines. Other potential, but less well ascertained interactions may involve the narcotic analgesics, caffeine, ethanol, pentobarbital, imipramine, chlormethiazole, and metronidazole. In these settings, the clinician must be aware of interaction potential, and astutely monitor the patient during combination therapy. Other data indicate that concomitant administration of antacids may reduce the absorption of cimetidine, that the drug may protect against the toxic effects of acetaminophen overdose, and that combination with certain other myelosuppressants may carry a significant risk. Thus, in regard to these reports, cimetidine is a drug with complex effects on the absorption, elimination, and toxicity of other drugs. When used in the setting of multiple drug therapy, the clinician must be alert to potentially increased or decreased effects of the drugs mentioned in this review. In addition, one must be aware that other hepatically metabolised agents not mentioned here may be affected by the addition of cimetidine therapy. Because of the therapeutic successes demonstrated in the treatment of various disorders with cimetidine, one cannot disregard this agent. Thus, the responsibility for understanding and monitoring for the complex effects of this drug falls with the practicing physician.

Clinical pharmacokinetics of cimetidine.

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 (Vd beta 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 microgram/ml (range 0.64-1.64 micrograms/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.(ABSTRACT TRUNCATED AT 400 WORDS)

Antacids inhibit absorption of cimetidine.

CURRENT recommendations for the treatment of peptic-ulcer disease call for cimetidine to be given with meals and at bedtime1 and for antacids to be taken between meals and at bedtime.2 Thus, these two medications may frequently be taken together at bedtime. In addition, many patients undoubtedly ingest cimetidine and antacids simultaneously during the day for the sake of convenience. Despite this practice, there is little information about whether or not commonly prescribed antacids available in the United States interfere with the absorption of cimetidine. Three European investigations have reported conflicting results regarding the effect of antacids on the bioavailability of . . .

Drug interactions with cimetidine.

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.

Influence of phenobarbital treatment on cimetidine kinetics.

The pharmacokinetics of orally administered cimetidine was studied in 8 healthy subjects before and after 3 weeks of treatment with phenobarbital 100 mg daily, and in a separate study 4 subjects received cimetidine intravenously before and after the administration of phenobarbital. There was no change in the volume of distribution, but total plasma clearance was increased by a mean of 18%, mainly due to a 37% increase of nonrenal clearance. Renal clearance and half-life were not significantly altered. The area under the plasma concentration-time curve after oral administration was significantly (P less than 0.05) reduced by a mean of 15% after phenobarbital treatment. The amount of cimetidine excreted in urine and its sulphoxide metabolite were significantly (P less than 0.05) reduced, on average by 34% and 26%, respectively by phenobarbital treatment. The data indicate that an apparent 20% reduction in the absorption of cimetidine was due to induction of gastrointestinal metabolism of cimetidine, with some contribution also from hepatic metabolism. Reduced absorption per se could not be totally excluded. Although the magnitude of the change was small, the finding of an 11% decrease in the time to achieve an effective plasma level of cimetidine after phenobarbital treatment may contribute to the ineffectiveness of cimetidine in certain patients.

Impaired cimetidine absorption due to antacids and metoclopramide.

In 8 healthy subjects the absorption of cimetidine was investigated when given alone, together with 60 ml aluminium/magnesium hydroxide containing antacid (neutralising capacity 26 mmol HCl/10 ml), and together with liquid metoclopramide 14 mg. The antacid significantly (P less than 0.01) reduced the bioavailability (area under the plasma level-time curve) of cimetidine, on average by one third. Metoclopramide also reduced the bioavailability by an average of 22%. The reductions were associated with significantly reduced excretion of cimetidine in urine. There was no change in the half-life or renal clearance of cimetidine, supporting the hypothesis of reduced gastrointestinal absorption. The results indicate that cimetidine and antacids should not be given together, and that the dose of cimetidine may have to be increased if it is administered concomitantly with metoclopramide.

Concurrent administration of cimetidine and enteric‐coated prednisolone: effect on plasma levels of prednisolone.

British Journal of Clinical PharmacologyVolume 10, Issue 1 p. 87-89 Free Access Concurrent administration of cimetidine and enteric-coated prednisolone: effect on plasma levels of prednisolone. PJ Morrison, PJ MorrisonSearch for more papers by this authorHJ Rogers, HJ RogersSearch for more papers by this authorID Bradbrook, ID BradbrookSearch for more papers by this authorC Parsons, C ParsonsSearch for more papers by this author PJ Morrison, PJ MorrisonSearch for more papers by this authorHJ Rogers, HJ RogersSearch for more papers by this authorID Bradbrook, ID BradbrookSearch for more papers by this authorC Parsons, C ParsonsSearch for more papers by this author First published: July 1980 https://doi.org/10.1111/j.1365-2125.1980.tb00506.xCitations: 15AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References BODEMAR, G., NORLANDER, B., FRANSSON, L. & WALEN, A. (1979). 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. Pharmac., 7, 23– 32. BRECKENRIDGE, A.M., CHALLINER, M., MOSSMAN, S., PARK, B.K., SERLIN, M.J., SIBEON, R.G., WILLIAMS, J.R.B. & WILLOUGHBY, J.M.T. (1979). Cimetidine: interaction with warfarin in man. Br. J. clin. Pharmac., 8, 392– 393p. BURLAND, W.L., DUNCAN, W.A.M., HESSELBO, T., MILLS, J.G., SHARPE, P.C., HAGGIE, S.J. & WYLLIE, J.H. (1975). Pharmacological evaluation of cimetidine, a new histamine H2-receptor antagonist, in healthy man. Br. J. clin. Pharmac., 2, 481– 486. CONN, H.O. & BLITZER, B.L. (1976). Nonassociation of adrenocorticosteroid therapy and peptic ulcer. N. Engl. J. Med., 294, 473– 479. FISHER, P., HOUSE, F., INNS, P., MORRISON, P.J., ROGERS, H.J. & BRADBROOK, I.D. (1980). Effect of cimetidine on the absorption of orally administered tetracycline. Br. J. clin. Pharmac., 9, 153– 158. FRIED, J. & ZIETZ, S. (1973). Curve fitting by Spline and Akima methods: possibility of interpolation error and its suppression. Phys. Med. Biol., 18, 550– 558. GIBALDI, M. (1977). Biopharmaceutics and clinical pharmacokinetics, p. 49. Philadelphia: Lea & Febiger. KAMMERER, W.H., FREIBERGER, R.H. & RIVELIS, A.L. (1958). Peptic ulcer in rheumatoid patients on corticosteroid therapy. Arth. Rheum., 1, 122– 141. LEE, D.A.H., TAYLOR, G.M., WALKER, J.G. & JAMES, V.H.T. (1979). The effect of food and tablet formulation on plasma prednisolone levels following administration of enteric-coated tablets. Br. J. clin. Pharmac., 7, 523– 528. MORRISON, P.J., BRADBROOK, I.D. & ROGERS, H.J. (1977). Plasma prednisolone levels from enteric and non-enteric coated tablets estimated by an original technique. Br. J. clin. Pharmac., 4, 597– 603. RANDOLPH, W.C., OSBORNE, V.L., WALKENSTEIN, S.S. & INTOCCIA, A.T. (1977). High pressure liquid chromatographic analysis of cimetidine, a histamine H2-receptor antagonist in blood and urine. J. pharm. Sci., 66, 1148– 1150. STERNBERG, W., KING, C. & TOSKES, P. (1978). Cimetidine inhibits the absorption of protein-bound vitamin B12 but not crystalline vitamin B12. Gastroenterology, 74, 1099. Citing Literature Volume10, Issue1July 1980Pages 87-89 ReferencesRelatedInformation

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.

1 The absorption of a single oral dose of cimetidine taken on a fasting stomach or together with a meal was studied in 28 patients before and during 12 weeks treatment with cimetidine. 2 No significant changes in bioavailability were seen during treatment measured as the area under the blood concentration curve (AUC). 3 AUC after a single dose of 400 mg cimetidine was 2.05 times the area after a 200 mg dose. 4 There was a good correlation between AUC and the dose of cimetidine given corrected for body weight (r=0.89). 5 There was no difference in bioavailability if 200 mg cimetidine was taken on a fasting stomach or together with a beef steak meal. 6. During fasting conditions there was a peak in blood concentration at about one hour followed by a second unexplained peak during the third to fifth hour after dose administration. 7 With food the initial rise in blood concentrations was slower and there was only one peak occurring about 2 h after dose administration.

Oral absorption of cimetidine and its clearance in patients with renal failure

The plasma concentration curve after a single oral dose of cimetidine 200 mg was followed in 27 patients with varying degrees of chronic renal failure (creatinine clearance 1--52 ml/min) and in 46 patients with normal serum creatinine. Compared to the latter patients, the plasma concentration was higher and the elimination rate was slower in all uraemic subjects, including a group with moderate renal impairment. The preliminary recommendations of dosage for patients with a creatinine clearance below 5 ml/min, and for patients on regular haemodialysis, is cimetidine 200 mg every 12 h, 5-15 ml/min 200 mg every 12 to 8 h, 15-30 ml/min 200 mg every 8 h and 30-52 ml/min 200 mg every 6 h.

Effect of Cimetidine on Serum Gastrin and Gastric Emptying in Man

Paired studies of gastric emptying were performed in 10 healthy volunteers using a scintiscanning technique which provides information about the rate of emptying of both the liquid and solid components of a standard meal. Emptying rates of both components were not significantly different after oral administration of 400 mg cimetidine than after placebo. The increase in serum gastrin concentration produced by the meal was significantly greater after cimetidine than after placebo but there was no relationship between individual cimetidine-placebo differences in gastrin response and the corresponding cimetidine-placebo differences in rates of emptying. A positive correlation was demonstrated between the gastric emptying rate of the liquid component and the 1 h cimetidine absorption, indicating that normal individual variation in gastric emptying is probably responsible for much of the normal individual variation in the rate of cimetidine absorption.

24-hour intragastric acidity and nocturnal acid secretion in patients with duodenal ulcer during oral administration of cimetidine and atropine.

Cimetidine markedly inhibits gastric acid secretion, but from the therapeutic point of view it is important to know whether concurrent treatment with an anticholinergic increases its effect. This possibility has been investigated by measuring the 24 h intragastric acidity and nocturnal output of acid in four duodenal ulcer patients, each receiving on separate occasions cimetidine 1 g/day and placebo, atropine 2-4 mg/day and placebo, cimetidine and atropine, or two placebos. Cimetidine alone decreased mean hourly hydrogen ion activity by 63% of control values, decreased mean hourly hydrogen ion concentration (total acid) by 41%, inhibited nocturnal acid secretion by 83% and resulted in half the nocturnal samples being anacidic. Atropine alone had no effect when compared with control and combined treatment with both drugs was not superior to cimetidine alone. Atropine did not affect the absorption or urinary excretion of cimetidine. Fasting serum gastrin concentrations were not changed by any of the treatments. At the doses studied, the combination of cimetidine with an anticholinergic appears to offer no advantages over treatment with the H2-antagonist alone. Cimetidine is the only potent anti-secretory drug that does not cause acute side-effects and this important advantage would be lost if it were given with a maximal dose of an anticholinergic.

Influence of a meal on the absorption of cimetidine. A new histamine H2-receptor antagonist.

Absorption of an oral dose of 300 mg of Cimetidine was studied after an overnight fast in six healthy male volunteers on three separate occasions, 20 min before, during, and 2 h after a standard breakfast. Compared to the doses taken before and after the meal, the dose taken with the meal showed a significant delay in the time taken to reach therapeutic blood concentrations of the drug with no reduction in the period of time during which this concentration was maintained. We, therefore, suggest that the drug should be taken with a meal to achieve optimal acid inhibition in the interdigestive period.