EFFECT OF CIMETIDINE ON THE ABSORPTION OF ORALLY ADMINISTERED TETRACYCLINE

Transcription

1 Br. J. clin. Pharmac. (198), 9, EFFECT OF CIMETIDINE ON THE ABSORPTION OF ORALLY ADMINISTERED TETRACYCLINE P. FISHER, F. HOUSE, P. INNS, P.J. MORRISON, H.J. ROGERS & 1I.D. BRADBROOK Departments of Pharmacology and Clinical Pharmacology and 'Forensic Medicine, Guy's Hospital Medical School, London SEI 9RT 1 Six healthy female subjects received orally two 25 mg tetracycline tablets either with 4 mg cimetidine or placebo. In a separate experiment six healthy female volunteers received 5mg tetracycline as a suspension on the fifth day of a 6 day regime of 4 mg cimetidine or placebo, 8 hourly and at bedtime. 5 mg tetracycline as tablets was also given with cimetidine only. 2 Following a single dose of cimetidine the mean peak tetracycline plasma concentration was significantly reduced by 1.2 1tg/ml and the area under the plasma concentration, time curve was decreased by 4%. The 72 h urinary tetracycline excretion was diminished by approximately 3%. 3 Tetracycline had no effect on the plasma concentration, time profile of cimetidine. 4 Administration of 4 mg cimetidine 8 hourly and at night for 6 days and dosing with 5 mg tetracycline as tablets or suspension on the fifth day produced no alteration in tetracycline kinetics. 5 It was concluded that under clinical circumstances it is unlikely that cimetidine produces a clinically significant alteration in tetracycline absorption or disposition. 6 The bioavailability of tetracycline from tablets and suspension was found to be similar (31.2% and 36.9% of the dose excreted in the urine over 72 h). 7 The mean renal clearance of tetracycline was 83.8 ml/min (95% confidence interval ml/min) and was unaltered by cimetidine treatment. Introduction The efficacy of the histamine H2-receptor blocker cimetidine in the short-term treatment of duodenal (Winship, 1978) and gastric (Freston, 1978) ulcers has now been established but it is also possible that maintenance treatment extending over many months will be needed by some patients. It is therefore likely that some of these patients may receive other drug therapy simultaneously with cimetidine. Drug interactions may occur whenever two drugs are concurrently administered and one (or both) drugs may influence the time course or extent of absorption of the other. Antacids are known to alter the absorption of other drugs (Hurwitz, 1977). Since cimetidine alters gastric acid secretion and therefore the ph of the stomach contents, there are theoretical reasons for anticipating interactions with this agent. The bioavailability of tetracycline from capsules has been demonstrated by many investigators to depend upon formulation factors (Barr, Gerbracht, Letcher, Plaut & Strahl, 1972; Barnett, Smith, Greenwood & Hetherington, 1974). Barr et al. (1972) found that concurrent administration of sodium bicarbonate, as distinct from antacids containing chelatable cations, reduced tetracycline absorption and suggested that elevated intragastric ph can retard tetracycline dissolution so decreasing the amount of dissolved tetracycline available for absorption in the small intestine. Studies were therefore undertaken to determine whether raising the intragastric ph with cimetidine would similarly interfere with absorption of tetracycline. Such an interaction, if it occurred, could have clinical significance since it might reduce the plasma and tissue tetracycline concentrations to levels below the minimum inhibitory concentration of the microorganism under treatment. We have also taken the opportunity to compare the bioavailability of tetracycline tablets and tetracycline suspension since little data is available on this latter formulation. Methods Two separate studies were carried out in seven normal, healthy female volunteers (mean age /8/ $1. C) Macmillan Joumals Ltd 198

2 154 P. FISHER, F. HOUSE, P. INNS, P.J. MORRISON, H.J. ROGERS & I.D. BRADBROOK years, range 23 to 32 years; mean weight 55.5 kg, range 45 to 8 kg). These subjects were screened clinically and had normal haematological and biochemical investigations. Each gave written consent to take part in the studies, the protocol of which had been approved by the Hospital Ethical Committee. No subject was taking any regular medication. Study 1 was a single dose crossover. Six subjects participated and were studied on three separate occasions with an interval of at least 7 days between each study day; Subjects were randomly assigned to the following regimes: (i) Cimetidine 4mg, as two 2mg TagametR (SK & F, Welwyn Garden City, Herts) tablets. (ii) Tetracycline 5 mg, as two 25 mg AchromycinR (Lederle, Gosport, Hants) tablets. (iii) Cimetidine 4 mg plus tetracycline 5 mg. Alcohol was not permitted for 48 h prior to any treatment or for 4 days following treatment. Smoking was not allowed for 8 h following administration of tetracycline and fat and dairy products were excluded from the diet on treatment days. On each study day the subjects reported to the laboratory in a fasting state and were given a standard breakfast of toast, marmalade and decaffeinated coffee (approximately 3 ml). When cimetidine is given with food, although the peak plasma level is slightly delayed, its bioavailability is unchanged (Bodemar, Norlander, Fransson & Walan, 1979). A venous blood sample was then taken as analytical control and the subjects then received the appropriate treatment as a single dose with 1 ml water. The exact time of dosing was recorded. Additional 1 ml volumes of water were given hourly for the first 3 h of the study. A standard meal (within subjects) was given 4 h after dosing. Blood samples were taken for cimetidine analysis at.25,.5, 1, 1.5, 2, 2.5, 3, 4, 5 and 6h and for tetracycline analysis at 1, 2, 3, 4, 5, 6, 8, 1, 12 and 24 h. Complete urine collections for 72 h after taking tetracycline were made. Study 2 was a double-blind crossover with a cimetidine placebo. Each of six subjects was studied on three separate occasions with an interval of at least 7 days between each study period. Subjects were randomly allocated to the following regimens:- (i) Following 5 days dosing with cimetidine 4 mg three times daily and 4 mg at night, subjects received 5 mg tetracycline as tablets. Cimetidine treatment was continued for a further 24 h following tetracycline administration. (ii) Following 5 days cimetidine treatment which was continued throughout the subsequent 24 h, subjects received 5 mg tetracycline in a syrup formulation of tetracycline suspension (Achromycin syrup, Lederle, Gosport, Hants. This contains 125 mg tetracycline hydrochloride in 5 ml). (iii) Following 5 days treatment with matching cimetidine placebo tablets, subjects received 5 mg tetracycline syrup. The method of study did not otherwise differ from study 1. Placebo tablets had maize starch as their main constituent and were coloured and coated to produce an identical appearance to TagametR tablets. Only five subjects were available to complete both studies. Assay of tetracycline was by the spectrophotofluorimetric technique of Kohn (1961) which extracts tetracycline from biological fluids as a barbiturate complex of a calcium tetracycline chelate. This is specific for tetracycline: metabolites and decay products do not interfere with the estimation. Measurements were made on an Aminco-Bowman fluorimeter using an excitation wavelength of 4 nm and an emission wavelength of 51 nm. The useful range of the assay in plasma is from.1 pg/ml to 5.g/ml with an inter-assay coefficient of variation of single observations about the mean 7.5%. Assay of cimetidine was carried out by a HPLC method using U-V detection (Randolph, Osborne, Walkenstein & Intoccia, 1977) by the Biochemistry Department, Smith Kline & French Research Ltd, Welwyn Garden City, Herts. All blood samples were analysed in duplicate with a coefficient of variation between duplicates of 3%. Pharmacokinetic analysis The plasma concentration, time data was best fitted to a one compartment open pharmacokinetic model with first-order elimination represented by the equation Ct = (kak) (exp (-ka (t-td)-exp (-ke (t-td) (1) where ka and ke are respectively absorption and elimination rate constants, td is the time delay before absorption commences, M is a constant involving the amount absorbed and the volume of distribution, and Ct is the plasma concentration at time t. This was fitted to the data using a digital computer although the procedure was complicated by the presence of discontinuities and local minima in the sum of squares function and it was found necessary to use more than one algorithm. This was particularly the case with the cimetidine data which sometimes exhibited the double peak in the plasma concentration, time profile discussed by Bodemar, et al. (1979). Areas were estimated by the trapezoidal rule, supplemented in the tail region by the

3 CIMETIDINE AND TETRACYCLINE ABSORPTION 155 M 3 c ci o Time (h) Figure 1 Tetracycline plasma concentrations (mean + s.d.) for six subjects following oral administration of 5 mg with () and without () 4 mg cimetidine. approximation Ct Ctdt= k' te where C* is the last measured plasma drug concentration at time t*. Areas were also calculated using the completely model-independent spline- Akima approximation (Fried & Zietz, 1973). This gave results essentially similar to those obtained by trapezoidal interpolation. An estimate of the time (ti) to attain the maximum plasma concentration (Cmax) was calculated from 1 k~ a ke ke t kk In ka+td (2) and Cmax was detennined from equation (1). Results The effect of co-administration of a single dose of cimetidine on the absorption of a single dose of 5 mg tetracycline is illustrated in Figure 1. Table 1 shows the phannacokinetic parameters estimated from the individual data. The significance of the observed differences in these parameters was assessed by paired Student's t-tests. Cimetidine produced no change in the elimination rate constant, and therefore half-life, of tetracycline but the mean peak tetracycline plasma concentration was reduced by 1.2 tg/ml or about 4% and the time to reach this peak was reduced by approximately 5 min or 25%. Cimetidine also decreased the area under the plasma concentration, time curve (AUC) for tetracycline by about 4%. Table 1 also shows that the urinary excretion of tetracycline over 72 h was decreased by about 3% by cimetidine. The relationship between the AUC for cimetidine and the changes in the various measurements of tetracycline absorption were explored by regression but no significant correlation was detected between the amount of cimetidine absorbed by the individual subjects and the altered tetracycline kinetics. Figure 2 shows that tetracycline has no effect on the plasma concentration, time profile of cimetidine. The results of mimicking the clinical situation with chronic cimetidine administration and a single dose of tetracycline (study 2) are somewhat different, and are shown in Table 2. The mean plasma concentration, time curves are shown as Figure 3. There was a large variation in the absorption of tetracycline both within and between subjects. Analysis of variance found no significant difference in the plasma tetracycline concentrations from any of the three treatments (P>.2). Comparison of the 72 h urinary tetracycline excretion for the five subjects who completed both experiments when a tablet formulation was given alone and with chronic cimetidine showed no significant difference (t =.955 for 4 degrees of freedom). The 72 h urinary tetracycline excretion (Qu72) is related to the area under the plasma concentration, time curve by QU72 = urinary clearance x AUC and this relationship is plotted in Figure 4. The least Table I Pharmacokinetic parameters for tetracycline and cimetidine and urinary tetracycline excretion estimated in six subjects from a single administration of 5 mg tetracycline with and without 4 mg cimetidine. ke (h -) T (h) ALJC (tg ml- 1 h) tm (h) Ciax (jg ml 1) 72 h urinary excretion (mg) * P<.5, ** P<.1 Tetracycline Cimetidine Alone + Cimetidine Alone + Tetracycline Mean s.d. Mean s.d. Mean s.d. Mean s.d * ** * * 38.9

4 156 P. FISHER, F. HOUSE, P. INNS, P.J. MORRISON, H.J. ROGERS & I.D. BRADBROOK m 2.-.)1.5- E Time (min) Figure 2 Cimetidine plasma concentrations (mean + s.d.) for six subjects following oral administration of 4 mg with () and without (U) 5 mg tetracycline. squares line of best fit forced through the origin gives a renal clearance of 83.8 ml/min (95% confidence interval of the slope ml/min). There were no significant differences observed between renal clearances of tetracycline derived from the different preparations as deternined by separate plots for each formulation. Discussion Cimetidine is a potent inhibitor of stimulated gastric acid secretion (Burland, Duncan, Hesselbo, Mills, Sharpe, Haggie & Wyllie, 1975). The absorption of tetracycline is preceded by dissolution of drug particles. This proceeds more rapidly at the low ph of the stomach since the equilibrium solubility of tetracycline hydrochloride is better than a hundredfold greater at ph 1.9 than at ph 5.5 (Barringer, Schultz, Sieger & Nash, 1974). Absorption of tetracycline takes place predominantly in the duodenum because of the lipophilicity of dissolved tetracycline at duodenal ph (Colaizzi & Klink, 1969). Barr, Adir & Garrettson (1971) found that when tetracycline was given in conjunction with sodium bicarbonate the absorption of the antibiotic was significantly reduced. Their suggested explanation for this phenomenon was that a raised intragastric ph is unfavourable to drug dissolution and this process may be incomplete so that the fraction of total drug absorbed will be decreased. It would therefore be reasonable to expect that increasing the intragastric ph with cimetidine might also reduce bioavailability. The present study has found a reduced tetracycline absorption following a single dose of cimetidine but this did not occur when cimetidine was administered on a chronic basis preceding a test dose of tetracycline. A recent study of tetracycline absorption in elderly patients with chronic achlorhydria (Kramer, Chapron, Benson & Mercik, 1978) has also failed to demonstrate interference with tetracycline absorption. These authors postulated that elevated ph only alters tetracycline bioavailability when preparations with marginal bioavailability and a potential for phinduced dissolution problems in vivo are used. Nevertheless, our single dose experiment shows a reduced tetracycline absorption similar to that demonstrated with a single dose of co-administered sodium bicarbonate whilst our experiment using repeated doses of cimetidine, which may be more analogous to an achlorhydric state, showed no important changes in tetracycline bioavailability. It should also be mentioned here that Kramer et al. (1978) were also unable to demonstrate any decrease in tetracycline bioavailability in two normal subjects given bicarbonate and tetracycline. The variability of tetracycline plasma levels is well recognized but its causes are largely undetermined. Factors which are known to be important include exercise (Ylitalo, Hinkka & Neuvonen, 1977), sleep (Adir & Barr, 1977) and food (Welling, Koch, Lau & Craig, 1977). The existence of this inherent variability requires that alterations in bioavailability produced by concurrent administration of other drugs should be relatively large to achieve statistical and clinical significance. Table 2 Pharmacokinetic parameters and urinary excretion of tetracycline estimated in six subjects following administration of 5 mg tetracycline as tablets or suspension preceded by cimetidine 4 mg, 6 hourly and at night, for 6 days or placebo. ke (h-1) T7 (h) AUC (jig ml- 'h) tm (h) Cmax (jg ml ') 72 h urinary excretion (mg) 72 h urinary excretion as % dose Tetracycline tablets and cimetidine Tetracycline suspension Tetracycline suspension and cimetidine Mean s.d. Mean s.d. Mean s.d

5 CIMETIDINE AND TETRACYCLINE ABSORPTION ( Time Ih) Figure 3 Mean tetracycline plasma concentrations for six subjects following oral administration of 5 mg tetracycline (a) as tablets after cimetidine 1.6 g daily for 5 days (), (b) as suspension after cimetidine 1.6 g daily for 5 days (OJ), (c) as suspension without cimetidine pretreatment (). The bioavailability of tetracycline from these various preparations may be estimated from the 72 h urinary excretion of drug. For tetracycline administered as a tablet a mean of 31.2% (s.d. 9.5%) of the dose was excreted in the urine over 72 h. For the suspension the corresponding value was 36.9% (s.d. 9.8%). These values were not significantly different, suggesting that tetracycline availability is similar from the two formulations. These bioavailability estimates are comparable with the values of 23.7% and 28.4% determined by Bergan, Oydvis & Lunde (1973) for two different commercial tetracycline preparations but less than the 49.3% determined by Barr et al. (1972) suggesting that the conjecture of Kramer et al. (1978) regarding the influence of achlorhydria on the bioavailability of preparations of lower availability may be invalid. Because of the relative age of tetracycline, bioavailability and other pharmacokinetic information relating to tetracycline suspensions has never been gathered. Helmi, Elian, Mustafa, El- Sayed & El-Razeky (1969) investigated the availability of an experimental tetracycline hydrochloride suspension in three subjects and found that absorption from the suspension was irregular and that bioavailability of tetracycline was reduced. Our data confirms the variability of absorption from the commercially available suspension used in the present experiments but suggests that the availability of tetracycline is not significantly different to that from a tablet formulation. The plasma half-life of tetracycline observed in the present study is comparable with that determined in other studies (e.g. Kramer et al., 1978). The renal clearance estimation may be compared with the mean 11 value of 88.1 ml/min determined by Barr et al. (1971) in five subjects but is a little higher than the estimate of 64 ml/min/1.73 m2 of Kramer et al. (1978). Administration of tetracycline with cimetidine does not apparently alter the disposition of that compound. The T, of cimetidine determined in these studies following oral administration may be related to the value of 1.78 h found following intravenous cimetidine administration by Griffiths, Lee & Taylor (1977). An explanation of the differing effects on tetracycline absorption obtained in the two studies presented here is not obvious. In some single dose studies cimetidine has not been shown to alter gastric emptying rate or pancreatic or biliary secretion (Heading, Logan, McLoughlin, Lidgard & Forrest, 1977; Longstreth, Go & Malagelada 1977). A more recent study (Forrest, Fettes, McLoughlin & Heading, 1978) in which duodenal ulcer patients were studied before, during and after chronic cimetidine therapy showed that although this treatment increased the emptying of both solid and liquid components of a meal, only the former achieved statistical significance. As acid is an inhibitor of gastric emptying, it is possible that inhibition of its secretion results in a differential effect on the rate of emptying of the two components of the meal. These results are in contrast to the acute effects of metiamide which retards gastric emptying (Forrest, Heading, Park, Carter, Lennon, Lidgard & Shearman, 1976). The changes occurring in gastric and intestinal physiology which result from chronic cimetidine administration and allow greater dissolution and availability of tetracycline remain to be investigated. The important practical implication of these studies is that chronic administration of C) E c CD xa).n r-. o 8,,,p o AUC (jug ml-'h) Figure 4 Relationship between cumulative urinary excretion of tetracycline over 72 h and the area under the plasma concentration, time curve (AUC) for all subjects and both studies. I

6 158 P. FISHER, F. HOUSE, P. INNS, P.J. MORRISON, H.J. ROGERS & I.D. BRADBROOK cimetidine does not appear to produce any clinically significant difference in tetracycline absorption or disposition. We are grateful to Dr R.I. Gleadle, Dr J. Horton and Mrs F. Storari of Smith, Kline & French for their assistance and support with these studies. References ADIR, J. & BARR, W.H. (1977). Effect of sleep on bioavailability of tetracycline. J. pharm. Sci., 66, BARNETT, D.B., SMITH, R.N., GREENWOOD, N.D. & HETHERINGTON, C. (1974). Bioavailability of commercial tetracycline products. Br. J. clin. Pharmac., 1, BARR, W.H., ADIR, J. & GARRETTSON, L. (1971). Decrease of tetracycline absorption in man by sodium bicarbonate. Clin. Pharmac. Ther., 12, BARR, W.H., GERBRACHT, L.M., LETCHER, K., PLAUT, M. & STRAHL, N. (1972). Assessment of the biologic availability of tetracycline products in man. Clin. Pharmac. Ther., 13, BARRINGER, W.C., SCHULTZ, W., SIEGER, G.M. & NASH, R.A. (1974). Minocycline hydrochloride and its relationship to other tetracycline antibiotics. Am. J. Pharm., 146, BERGAN, T., YDVIS, B. & LUNDE, I. (1973). Biological availability and in vitro release from oral oxytetracycline and tetracycline preparations. Acta Pharmac. Tox., 33, BODEMAR, G., NORLANDER, B., FRANSSON, L. & WALAN, A. (1979). The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidinestudies in patients with peptic ulcer disease. Br. J. clin. Pharmac., 7, 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, COLLAIZZI, J.L. & KLINK, P.R. (1969). ph partition behaviour of tetracyclines. J. pharm. Sci., 58, FORREST, J.A.H., HEADING, R.C., PARK, J., CARTER, D.C., LENNON, J., LIDGARD, G. & SHEARMAN, D.J.C. (1976). Effect of histamine H2-receptor blockade on gastric emptying and serum gastrin in man. Scot. med. J., 21, FORREST, J.A.H., FETTES, M., McLOUGHLIN, G. & HEADING, R.C. (1978). The effect of long term cimetidine on gastric acid secretion, serum gastrin and gastric emptying. In Cimetidine: the Westminster Hospital Symposiwn, Eds Wastell, C. & Lance, P. Churchill Livingstone. pp London. FRESTON, J.W. (1978). Cimetidine in the treatment of gastric ulcer. Review and commentary. Gastroenterology, 74, FRIED, J. & ZIETZ, S. (1973). Curve fitting by Spline and Akima methods: possibility of interpolation error and its suppression. Phys. Med. Biol., 18, GRIFFITHS, R., LEE, R.M. & TAYLOR, D.C. (1977). Kinetics of cimetidine in man and experimental animals. In Cimetidine: Proceedings of the Second International Symposiwn on histamine H2-receptor antagonists, Ed Burland, L.W. & Simkins, M.A. pp Amsterdam: Excerpta Medica. HEADING, R.C., LOGAN, R.F.A., McLOUGHLIN, G.P., LIDGARD, G. & FORREST, J.A.H. (1977). Effect of cimetidine on gastric emptying. In Cimetidine: Proceedings of the Second International Symposiwn on histamine H2-receptor antagonists, Eds Burland, L.W. & Simkins, M.A. pp Amsterdam: Excerpta Medica. HELMI, R., ELIAN, A., MUSTAFA, M., EL-SAYED, H.I. & EL-RAZEKY, S. (1969). Influence of different pharmaceutical forms on the efficiency of tetracycline. J. Egyptian Med. Ass., 52, 392. HURWITZ, A. (1977). Antacid therapy and drug kinetics. Clin. Pharmacokin. 2, KOHN, K.W. (1961). Determination of tetracyclines by extraction of fluorescent complexes. Application to biological materials. Analyt. Chem., 33, KRAMER, P.A., CHAPRON, D.J., BENSON, J. & MERCIK, S.A. (1978). Tetracycline absorption in elderly patients with achlorhydria. Clin. Pharmac. Ther., 23, LONGSTRETH, G.F., GO, V.L.W. & MALAGELADA, J-R. (1977). Postprandial gastric, pancreatic and biliary response to histamine H2-receptor antagonists in active duodenal ulcer. Gastroenterology, 72, 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, WELLING, P.G., KOCH, P.A., LAU, C.C. & CRAIG, W.A. (1977). Bioavailability of tetracycline and doxycycline in fasted and non-fasted subjects. Antimicrob. Agents Chemother., 11, WINSHIP, D.H. (1978). Cimetidine in the treatment of duodenal ulcer. Review and commentary. Gastroenterology, 74, YLITALO, P., HINKKA, H. & NEUVONEN, P.J. (1977). Effect of exercise on the serum level and urinary excretion of tetracycline, doxycycline and sulphamethizole. Eur. J. clin. Pharmac., 12, (Received April 19, 1979)