Br. J. clin. Pharmac. (1987), 24, 551-553

Effects of antacids and food on absorption of famotidine

J. H. LIN, A. N. CHREMOS, S. M. KANOVSKY, S. SCHWARTZ, K. C. YEH & J. KANN Merck Sharp and Dohme Research Laboratories, West Point, PA 19486 and Biodecision Laboratories, Inc. Pittsburgh, PA 15213, USA

The effect of a high potency antacid and food on the bioavailability of famotidine was studied in 17 healthy volunteers in an open randomized three-way cross-over trial. After an overnight fast, famotidine was administered to each subject as follows: 40 mg famotidine orally alone; 40 mg orally with antacid; and 40 mg orally with a standard breakfast. Co- administration of the antacid caused a small but significant reduction in the maximum plasma concentration (Cmax) of famotidine from 81.1 ± 54.2 to 60.8 ± 21.6 ng ml-' (P < 0.05) and a small decrease in the area under plasma concentration-time curve [AUC] from 443.3 ± 249.2 to 355.0 ± 125.1 ng ml-1 h (P > 0.05). However, there was only a minimal effect of food on these parameters; the Cmax and [AUC] were 81.6 ± 29.6 ng ml-' and 434.8 ± 145.9 ng ml-' h, respectively. Keywords famotidine antacids food absorption

Introduction Famotidine (3-(((2-((aminoiminomethyl)amino)- The purpose of the present study was to in- 4-thiazolyl)methyl)-thio)-N(aminosulphonyl)- vestigate the effects of a high potency antacid propanimidamide) is a new histamine H2- and food on the bioavailability and disposition of receptor antagonist. It has been reported to be famotidine. more potent than ranitidine and cimetidine in inhibiting gastric acid secretion (Pendleton et al., 1983). Renal excretion plays a substantial Methods role in the elimination of famotidine from the body. Earlier studies from our laboratory have Seventeen volunteers of either sex were each shown that the renal clearance of famotidine in studied on three occasions at least 1 week apart. man and rats was about three times the glomerular All subjects were in good health as judged by filtration rate, suggesting that famotidine might appropriate laboratory tests and clinical examin- be secreted by an active secretary mechanism ation. (Lin et al., 1987). After an overnight fast, they received the In the treatment of peptic ulcer disease ant- treatment of famotidine on three different acids are sometimes prescribed or self-admin- occasions separated by at least 1 week, famoti- istered concurrently with histamine H2-receptor dine alone (Treatment A), famotidine plus antagonists. Gugler et al. (1981) reported that Mylanta II (Treatment B) and famotidine plus a cimetidine absorption was reduced by co-admin- standard breakfast (Treatment C). The assign- istration with antacids. The absorption of raniti- ment of treatment sequences was randomized. dine has also been reported to be diminished by Famotidine was given in one 40 mg tablet. The antacids (Mihaly et al.,.1982). It was therefore of selected antacid (10 ml Mylanta II) is of high importance to investigate the effect of antacids potency and composed of 800 mg each aluminum on the bioavailability of famotidine. and magnesium hydroxide plus 60 mg simethicone Correspondence: Dr Jiunn H. Lin, Drug Metabolism, WP42-2, Merck Sharp and Dohme Research Laboratories West Point, PA 19486, USA 551 552 J. H. Lin et al. with an antacid neutralizing capacity of50.8 meq (1973) wherein the variability in renal excretion acid/10 ml of the liquid preparation. The stan- is considered. dard breakfast consisted of 4 ounces of orange Statistical analysis was performed by Fisher's juice, one bowl of Special Kg cereal, 130 ml low least significant difference test based on an fat milk and one fruit danish with one pat of analysis of variance which blocked only on sub- margarine. When famotidine was administered ject before testing treatment effects (Snedecor concurrently with Mylanta II, the antacid was & Cochran, 1974). P < 0.05 was considered to taken first and immediately followed by famoti- be significant. dine with 150 ml of water. In the study of food effect, the breakfast was eaten first and im- Results mediately followed by famotidine with 150 ml of water. When famotidine was administered alone, Co-administration with antacids caused a small it was also taken with 150 ml of water. but significant reduction in the maximum plasma Heparinized blood was collected at 0, 0.5, 1, concentration (Cm.1) for famotidine and a small 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24 and 48 h after decrease in the area under plasma concentration- drug administration. Urine was collected as per time curve (AUC) (Table 1). The time to reach the following schedule: -1 to 0 (pre-drug); 0-2, the peak concentration (tm.a) was somewhat 2-4, 4-6, 6-8, 8-12, 12-24, 24-36, and 36-48 h shorter in the presence of antacids. There was no post treatment. Plasma was immediately separ- significant effect of food on these parameters, as ated by centrifugation. Volunteers were in- shown by the similar values obtained for these structed to empty their bladder at the end of parameters after food compared with the fasting each collection period. The plasma and urine state (Table 1). The total amount excreted as stored at -20° C until assay. The concentrations unchanged famotidine was slightly reduced in of famotidine in plasma and urine were deter- the antacids study, whereas the urinary recovery mined by h.p.l.c. (Vincek et al., 1985). of unchanged drug tended to be higher with The renal clearance of famotidine was calcu- breakfast (Table 1). lated as the amount of unchanged famotidine The values for the renal clearance are practi- excreted in the urine over the period of time cally identical following all three treatments, (0-12 h) divided by area under plasma concen- suggesting that neither the antacid nor the food tration-time curve (AUC) over the same time has an effect on the renal excretion of famotidine. period. The ratio of bioavailability (relative bio- The mean bioavailability ratios of famotidine availability) of famotidine with co-administration with antacid, and with food to that of famotidine of antacids or food to that of famotidine alone alone were 0.90 and 1.14, respectively, suggest- was calculated by the method of Kwan & Till ing that antacids sli,ghtly reduced the extent of

Table 1 Area under plasma concentration-time curve (AUC), renal clearance, and maximum plasma concentrations (Cm.in) of famotidine and the time (tQmU) at which they were observed following treatment A, B, and C in healthy volunteers (n= 17) TreatmentA Treatment B" Treatment CC Cma, 81.1 60.8d 81.6 (ng ml-1) ±54.2 +21.6 ±29.6 tmax 2.62 2.24 2.44 (h) ±1.13 ±0.79 ±0.63 AUC (0-cc) 443.3 355.0 434.8 (ng ml-' h) ±249.2 +125.1 ±145.9 Renal clearance 25.8 27.9 28.5 (1h-1) ±10.5 ±125.1 ±145.9 Urinary recovery of 9.87 8.79 11.1 unchanged drug ±4.29 ±2.82 ±3.0 (mg) a Treatment A = famotidine 40 mg tablet. b Treatment B = famotidine 40 mg tablet and Mylanta II. c Treatment C = famotidine 40 mg tablet and standard breakfast. d Significantly different from Treatment A, P < 0.05. Short report 553 absorption offamotidine, while food had slightly the percentage of administered basic drugs that enhanced absorption. are dissolved when they pass into the small in- testine and hence increase their absorption. This may explain why there is a small increase in the Discussion absorption of famotidine when the drug was given with a standard breakfast. Antacids have been shown to decrease the bio- The unchanged values for renal clearance of availability of cimetidine (Gugler et al., 1981) famotidine after the three different treatments and ranitidine (Mihaly etal., 1982) to about 35% indicated that the renal excretion of famotidine in healthy volunteers. A similar effect, but to a was not affected by antacids or food. These smaller degree, was observed when an antacid results suggested that the observed reductions in was co-administered with famotidine. This was Cm. and AUC of famotidine after co-admin- shown by the reduced AUC and the comparable istration of antacids are due to the interaction reduction in the urinary recovery of unchanged between famotidine and antacids in the gastro- famotidine (Table 1). intestinal lumen, rather than the alterations in By raising the pH in the gastrointestinal tract, the elimination processes. antacids may decrease the solubility of bases, In conclusion, co-administration of the ant- such as famotidine, ranitidine and cimetidine. acids caused a small but significant decrease in Antacids may also absorb or chelate drug the Cm.x, and a small decrease in the AUC and molecules to form insoluble complexes and may the extent of absorption offamotidine, while the also indirectly affect the gastric emptying time. standard breakfast had an opposite effect. These Nevertheless, the exact mechanism ofthe reduc- effects are considered minor. Since famotidine is tion in the absorption of famotidine observed in a potent H2-receptor antagonist, the 10-15% this study is unclear. change in bioavailability is unlikely to be clinically Ingested food tends to delay stomach-emptying. relevant. Prolonged retention in the stomach may increase

References Gugler, R., Brand, M. & Somogyi, A. (1981). Impaired on MK-208 (YM-11170), a new slowly dissoluable cimetidine absorption due to antacids and meto- H2-receptor antagonist. Arch. int. Pharmacodyn. clopramide. Eur. J. clin. Pharmac., 20, 225-228. Ther., 266, 4-16. Kwan, K. C. & Till, A. E. (1973). Novel method for Snedecor, M. & Cochran, G. (1974). Statistical bioavailability assessment. J. pharm. Sci., 62, methods (sixth edition), p. 272. Iowa State Univer- 1494-1497. sity Press. Lin, J. H., Los, L. E., Ulm, E. H. & Duggan, D. E. Vincek, W. C., Constanzer, M. L., Hessey, G. A., III (1987). Urinary excretion kinetics of famotidine in & Bayne, W. F. (1985). Analytical method for the rats. Drug Metab. Disp., 15, 212-216. quantification of famotidine, an H2-receptor blocker Mihaly, G. W., Marino, A. T., Webster, L. K., Jones, in plasma and urine. J. Chromatography, 338, 438- D. B., Louis, W. J. & Smallwood, R. A. (1982). 443. High dose ofantacid (Mylanta II) reduces bioavail- ability of ranitidine. Br. med. J., 285, 998-999. (Received 2 September 1986, Pendelton, R. G., Torchiana, M. L., Chung, C., Cooke, accepted 18 June 1987) P., Wiese, S. & Clineschmidt, B. V. (1983). Studies