The suppository form of antibiotic administration: pharmacokinetics and clinical application

E. Bergogne-Bérézina,* and A. Bryskierb

a Microbiology Department, Bichat-Claude Bernard University Hospital, 46 Rue Henri-Huchard, 75877 Paris Cedex 18; b Argenteuil Hospital, France


    Abstract
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 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
The rectal route of antibiotic administration might be used effectively when other routes of administration are inadequate or unsuitable. With the use of various adjuvants, the rectal route can provide satisfactory pharmacokinetics and acceptable local tolerance. Experiments in animals have demonstrated the influence of the pharmaceutical formulation of suppositories on the rectal absorption and systemic distribution of ß-lactams and aminoglycosides. In healthy volunteers and in children under treatment, similar adjuvants— mainly glyceride mixtures or non-ionic surface agents— have increased the rectal absorption of aminopenicillins, cephalosporins and macrolides. Other antibiotics, including metronidazole and co-trimoxazole, have been investigated in respect of their potential rectal administration.


    Introduction
 Top
 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
Antibiotics are usually administered either orally or by a parenteral route, the latter being used for drugs that are poorly or not bioavailable by the oral route or when clinical situations require rapid or higher antibiotic concentrations to be achieved in the body. The rectal route of antibiotic administration is seldom mentioned in experimental and clinical pharmacokinetic studies and the characteristics of administration of antibiotics by suppository is poorly documented.

There are significant differences between countries in terms of the acceptability of suppositories by patients, but, in some populations, rectal drug delivery could represent a convenient, alternative route of antibiotic administration when other routes are not available. This might occur in several situations : (i) when administration by the oral route results in intolerance, nausea, vomiting or gastric pain; (ii) when patients are uncooperative or have decreased consciousness; (iii) when access to the intravenous route is difficult, e.g. in children or in patients in intensive care units needing multiple drugs and continuous fluid infusions but with few veins undamaged; (iv) in ambulatory patients, when repeated, painful intramuscular administration of drugs is not well accepted. 1,2

This review deals with the available data on the pharmacokinetics and clinical efficacy of the suppository forms of antibiotics, as well as with the advantages and drawbacks of rectal antibiotic administration. Data collected from studies of rectal administration of preparations other than suppositories are also reported.


    Anatomical and physiological features
 Top
 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
In humans the rectum comprises the last 12–19 cm of the large intestine and the rectal epithelium is formed by a single layer of columnar or cuboidal cells and goblet cells; its surface area is about 200–400 cm2. The absorbing surface area of the rectum is considerably smaller than that of the small intestine, as the former lacks villi and microvilli. 2,3 However, the epithelia in the rectum and the upper intestinal tract are histologically similar, giving them comparable abilities to absorb drugs.1 The rectal mucosa is richly vascularized: this important blood supply comprises the inferior and middle veins, which are directly connected to the systemic circulation, and the superior rectal vein, which is connected to the portal system. This ensures that drugs in suppository form which are absorbed in the upper rectum will not by-pass the hepatic `first-pass' elimination, 4 responsible for the metabolism and rapid clearance of many orally administered drugs, such as the macrolides.

Since many experimental studies of rectal drug administration are performed in animals, it is necessary to note the differences in structure between human and animal rectums. In most animal species, histological analysis reveals more goblet cells in the rectal mucosa than in the colon; in rats and rabbits there are many lymph nodes in the lamina propria and submucosa. 5 The mucosa is also thrown into several longitudinal folds containing large veins: this structure seems favourable to local absorption of drugs. A rapid colorectal cell turnover has also been described, potentially stimulated by chemicals such as ethanol or isoenergetic carbohydrates6 but such response has not always been discussed in studies of antibiotic administration in rats or rabbits. 7,8,9


    Drug absorption in the rectum
 Top
 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
The mechanisms of rectal absorption of drugs are not significantly different from those in the upper part of the gastrointestinal tract. The rectal absorption of sulphonamides with perfusion techniques has been studied in rats; 7 these authors and some others 2,3 have concluded that, after rectal administration, passive transport is the main mechanism of absorption, that the absorption is mainly dependent on the molecular weight, liposolubility and degree of ionization of molecules, and that basic drugs are absorbed faster in the presence of anions like sodium lauryl sulphate. Hence, rectal absorption of drugs is governed largely by the general principles of transfer of antibiotics.10 Depending on their chemical structure, drugs may cross the rectal wall either by absorption across the epithelial cell (transcellular) or via the tight junctions interconnecting the mucosal cells (paracellular). 2 Several local host factors may influence absorption in the rectum: the mucous layer, the variable volume of rectal fluid, the basal cell membrane, the tight junctions and the intracellular compartments may each constitute local barriers to drug absorption, depending on histological factors and on the molecular structure of the administered drug. The pharmaceutical formulation, therefore, may play a major role in the rectal absorption and consequently in the systemic distribution and pharmacokinetics of antibiotics administered via suppository.


    Pharmaceutics of suppository form of antibiotics: experimental studies
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 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
Various pharmaceutical formulations are available or are under investigation for rectal delivery of antibiotics; these include suppositories, rectal capsules and enemas (solutions and suspensions). Many adjuvants have been proposed and experiments in animals have been carried out with various preparations. 9,11,12,13 Some agents may increase the absorption of the administered drug by improving mucosal permeability of poorly absorbed antibiotics, such as aminoglycosides or parenteral cephalosporins (Table I). The promoting effect of sodium salts of saturated straight-chain fatty acids on the rectal absorption of ampicillin and of ceftizoxime has been confirmed in mice, rats, rabbits and dogs with bioavailability rates higher in mice and rabbits (76–100%) than in dogs (28.9% and 42% for ampicillin and ceftizoxime, respectively 14). The fatty acid used in the latter study and in others 9 was sodium caprate, a carboxylic acid sodium salt, which improved the rectal absorption of poorly absorbed drugs such as ß-lactams. Several other fatty acid salts, e.g. sodium capronate, sodium caprylate and sodium palmitate, also improved the absorption of ampicillin but the best absorption-promoting effect was exhibited by sodium caprate, with satisfactory bioavailabilities of 71.3% and 64.2% for ampicillin and piperacillin, respectively. In the same study, the bioavailabilities of cephalosporins generally ranged between 60.6% (cefotiam) and 92.4% (cefazolin), with lower bioavailabilities for cefpiramide (26.2%) and cefoperazone (27.5%). It seems likely that the absorption-promoting effect on ß-lactams is stronger for antibiotics of smaller molecular size. 9 As summarized in Table I, various other absorption-promoters have been used in experiments in animals. For example, Witepsol H-15, a saturated triglyceride, has been used in suppositories of bacampicillin and compared with the same formulation of ampicillin. 15 For the rectal administration of latamoxef in rats, 16 the release rates from suppositories containing Witepsol H-15 only, or with the addition of Tween 80 (1%), with or without diclofenac sodium, a non-steroidal antiinflammatory drug, were compared. It was shown that the latter additions significantly increased the rectal absorption of latamoxef, with bioavailability as high as 72%.


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Table I. Experimental data on antibiotic administration by the rectal route
 
Various other commercially available preparations (e.g. glyceride mixture MGK), mainly composed of glyceryl-l-monooctanoate, glyceryl-1,3-dioctanoate and several other glycerides, have been assayed as absorption promoters (Table I). 17 Rectal infusion (over 30 min) produced more favourable parameters than bolus administration for cefazolin. Cefoxitin administered in a rectal solution including a glyceride mixture, 3-amino-1-hydroxy-propylidene-1,1-diphosphonate disodium salt (APD), provided a high rate of absorption, with 85% bioavailability, thanks to the enhancing effects of calcium-binding agents. 18 Several other studies in animals of the suppository route of administration of aminoglycosides have used similar preparations, with triglycerides (Witepsol H-15 or H-42) for gentamicin 11 or with medium-chain glycerides (Capmul) for gentamicin and tobramycin rectal administration, 19 resulting in enhanced absorption of aminoglycosides which are otherwise poorly absorbed.


    Pharmacokinetics of antibiotics administered by the rectal route in humans
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 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
A limited number of studies have been carried out in humans to determine pharmacokinetic parameters and bioavailability of antibiotics administered by the rectal route. The data collected from experiments in volunteers (generally adults) or in patients (children) receiving antibiotics are summarized in Table II. Only three main classes of antibiotic have been studied recently in respect of their rectal absorption and distribution; these are the ß-lactams, macrolides (erythromycin only) and imidazoles (tinidazole and metronidazole). Other antibiotics have been administered rectally but the data published for chloramphenicol or tetracyclines, for instance, are very old (1969–1972) and the usage of these drugs is, currently, very restricted.20


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Table II. Human studies on rectal bioavailability of antibiotics
 
ß-Lactams

Ampicillin and bacampicillin are the only penicillins that have been administered to humans in the suppository form or in the form of rectal microenemas. 21,22,23 Maximal plasma concentrations achieved in children after ampicillin administration by suppositories were 5.9 mg/L (range 4.8–7.0 mg/L) and 8.5 mg/L (range 6.0–11.0 mg/L) after 125 mg and 250 mg doses, respectively. These figures are well above the MIC values for most respiratory pathogens; in this particular study the authors 23 indicated a clinical effect of rectally administered ampicillin similar to that of orally administered amoxycillin. A comparison of bacampicillin bioavailability after oral or microenema administration (microenema) of 400 mg in 12 volunteers showed a much smaller degree of rectal absorption than that by the oral route: as seen in Table II the peak (6 S.D.) plasma concentration was 1.16 6 0.33 mg/L and 4.77 6 0.98 mg/L after rectal and oral administration respectively. 22

Two studies of rectal administration of cefoxitin in humans used different suppository forms containing adjuvants such as sodium salicylate or a nonionic surface-active agent, Brij 35, 24 or rectal infusion with the addition of sodium octanoate or sodium salicylate. 25 The bioavailability of cefoxitin was significantly increased in the presence of adjuvants; both octanoate and salicylate similarly increased cefoxitin absorption following rectal infusion in the same study.25

Erythromycin

Owing to frequent gastrointestinal side effects after oral administration of erythromycin, suppositories have been used often, particularly in childhood infections. The chemical details of the adjuvants contained in erythromycin suppositories were not provided in most of the available studies; the trade names of the preparations were Proterytrin (Proter SpA, Milan, Italy) 26 and Neo-Bismocetina (Le Petit). 27 Maximal serum concentrations achieved after rectal administration varied from 0.44 6 0.11 to 0.78 6 0.07 mg/L (250 mg dose) and were 0.35 6 0.03 mg/L after a 150 mg dose administered to children. 28 Proterytrin and Neo-Bismocetina formulations did not show any significant difference in bioavailability the highest serum levels were 0.53 6 0.04 and 0.49 6 0.10 mg/L, respectively. 27 One study examined the concentrations of erythromycin achieved in sputum after rectal administration of 500 mg erythromycin base and Proterytrin: mean concentrations were 0.23 6 0.03 mg/L 4 h after the administration, a ratio of 34.9% of simultaneous serum concentrations. 26

In one study 29 the relationship between age and the rectal bioavailability of erythromycin was established in three groups of children and the pharmacokinetic parameters were compared with those after intravenous administration: the data are shown in Table II. The bioavailability of erythromycin administered rectally increased from 28% in neonates to 36% in infants and up to 54% in children older than 1 year; this may be explained by a delayed absorption in neonates and by age-dependent systemic parameters.

In one study, the azalide, azithromycin, was administered (500 mg) to six volunteers by the rectal route, and the Cmax and AUC (mg/mL) obtained were compared with those obtained after iv administration. 30 The rectal route resulted in an extremely low Cmax (0.11 mg/L) and AUC (0.31 mg·h/L); the corresponding values for the iv route were 3.99 mg/L and 10.00 mg·h/L, respectively. The bioavailability achieved following administration by the rectal route was estimated as only 3.2%.

Imidazoles

Serum pharmacokinetics of different dosages of metronidazole have been compared after tablet and suppository administration. The results are summarized in Table II; they show that that the suppositories provided significant absorption, with AUC0-{chi} values not significantly lower than those achieved with tablets. The bioavailability of drug following administration by suppositories was 90% of that seen following administration by tablets.31 The bioavailability of tinidazole was compared with that of metronidazole and there was no significant difference between parameters established for both drugs administered in the suppository form at a dosage of 1 g. The serum pharmacokinetics for the two drugs were somewhat different after iv administration (500 mg infusion over 20 min) with a larger AUC0-{chi} for tinidazole (175.8 ± 12.7 mg·h/mL) than for metronidazole (106.9 ± 10.7 mg·h/mL). The longer half-life and larger volume of distribution for tinidazole supported either smaller doses or less frequent administration of tinidazole.32

Other antibiotics

The rectal administration of 960 mg of co-trimoxazole at 8 h intervals has resulted in serum concentrations comparable to those achieved after repeated oral administration of equivalent doses at 12 h intervals. 32 A more recent study investigated suppositories containing 480 mg co-trimoxazole with Witepsol H-15, with and without 10% Tween 60. 33 The bioavailability of the combination was assessed on the basis of urinary excretion. Suppositories of Witepsol H-15 incorporated with Tween 60 showed the highest absorption of trimethoprim and sulphamethoxazole and the authors recommended this formulation as a suppository base. The rectal absorption of lincomycin, 35 chloramphenicol 20 or tetracyclines 36 was investigated in early studies but the technical and analytical procedures used may not have been reliable enough to give accurate results. One recent study evaluated the pharmacokinetics of fluconazole given as 25 mg and 200 mg suppositories to volunteers and compared the results with those obtained after oral administration of the same doses as capsules or suspension. As seen in Table II, the pharmacokinetic parameters were very similar for both oral and rectal routes of drug administration. 37


    Discussion
 Top
 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
Although the rectal route of antibiotic administration is less commonly used today, and then only in some countries, it can be regarded as an important alternative way of drug delivery in several clinical situations in which other routes of administration are impracticable. The development of new formulations of suppositories has resulted in improved absorption and bioavailability of ß-lactams and aminoglycosides. The enhancing effect of Witepsol H15 (saturated triglycerides), Tween 60, Tween 80 or various saturated straight-chain fatty acids on the rectal absorption of antibiotics has been proven in animal experiments. However, extrapolation of data obtained in experimental studies in animals to the human situation remains questionable, owing to differences in the doses administered and to significant differences in intestinal structure, histology and physiology between rodents and humans.

Human studies are limited due to ethical constraints. For a small number of antibiotics it has been shown that the rectal route is as effective as the oral route of administration with similar pharmacokinetics after each route. 38 However, there is reluctance in some societies to adopt the rectal route of administration. In addition, there are significant side effects in some circumstances: prolonged rectal use of some drugs has been found to induce rectal ulceration, rectal bleeding and pain. 2,3 Even the suppository base or the enhancer may damage the rectal mucosa and cause local inflammation.2, 3,16 Further research into safer absorption-promoting agents may be necessary in order to `rehabilitate' the rectal route of antibiotic administration which may then offer a very useful alternative route in intensive-care-unit patients and in children.


    Notes
 
* Tel: +33-1-40-25-85-27; Fax: +33-1-42-28-99-51 Back


    References
 Top
 Abstract
 Introduction
 Anatomical and physiological...
 Drug absorption in the...
 Pharmaceutics of suppository...
 Pharmacokinetics of antibiotics...
 Discussion
 References
 
1 . De Boer, A. G., Moolenaar, F., de Leede, J. & Breimer, D. D. (1982). Rectal drug administration: clinical pharmacokinetic considerations. Clinical Pharmacokinetics 7,285 –311.[ISI][Medline]

2 . Van Hoogdalem, E. J., De Boer, A. G. & Breimer, D. D. (1991). Pharmacokinetics of rectal drug administration. Part 1. General considerations and clinical applications of centrally acting drugs. Clinical Pharmacokinetics 21, 11–26.[ISI][Medline]

3 . Moës, A. (1980). Biodisponibilité des formes d' administration rectale. Science and Technical Pharmaceutics 9, 263–88.

4 . Henrich, M. (1980). Clinical topography of the proctodeum. Acta Anatomica 106, 161–70.[ISI][Medline]

5 . Dellmann, H. D. & Brown, E. M. (1987). Textbook of Veterinary Histology, 3rd edn. Lea & Febiger, Philadelphia, PA.

6 . Simanowski, U. A., Suter, P., Russel, R. M., Heller, M., Waldherr, R., Ward, R. et al. (1994). Enhancement of ethanol induced rectal mucosal hyper-regeneration with age in F344 rats. Gut 35, 1102–6.[Abstract]

7 . Kakemi, K., Arita, T. & Muranishi, S. (1965). Absorption and excretion of drugs. XXV. On the mechanism of rectal absorption of sulfonamides. Chemical and Pharmaceutical Bulletin 13, 861–9.

8 . Bahia, M. F. (1991). Absorption of some cephalosporins by rectal route in rabbits. Bollettino Chimico Farmaceutico 130, 128–32.[Medline]

9 . Nishimura, K. I.,Nozaki, Y., Yoshimi, A., Nakamura, S., Kitagawa, M., Kakeya, N. et al. (1985). Studies on the promoting effects of carboxylic acid derivatives on the rectal absorption of ß-lactam antibiotics in rats. Chemical and Pharmaceutical Bulletin 33, 282–91.

10 . Curry, S. H. (1977). Drug Disposition and Pharmacokinetics with a Consideration of Pharmacological and Clinical Relationship, 2nd edn. Blackwell Scientific, Oxford.

11 . Matsumoto, Y., Watanabe, Y., Tojima, T., Murakoshi, R., Murakawi, C. & Matsumoto, M. (1989). Rectal absorption enhancement of gentamicin in rabbits from hollow type suppositories by sodium salicylate or sodium caprylate. Drug Design and Delivery 4, 247–56.[Medline]

12 . Yata, N., Higashi, Y., Murakami, T., Yamajo, R., Wu, W.M., Taku, K. et al. (1983). A possible mechanism of absorption promoters. Journal of Pharmacobiodynamics 6,S78 .

13 . Nishihata, T., Rytting, J. H., Higuchi, T., Caldwell, L. J. and Selk, S. J. (1984). Enhancement of rectal absorption of water-soluble antibiotics in dogs. International Journal of Pharmaceutics 21, 239–48.[ISI]

14 . Kakeya, N. (1985). Development of new adjuvants for enhanced rectal absorption. In Proceedings of the 14th International Congress of Chemotherapy, Kyoto, p. 2711.

15 . Kawashima, S., Nishiura, N.,Noguchi, T. & Fujiwara, H. (1989). Studies on sustained-release suppositories. Effect of alginic acid addition on rectal absorption of bacampicillin in rabbits. Chemical and Pharmaceutical Bulletin 37, 766–70.

16 . Nakanishi, K., Masukawa, T., Masada, M. & Nadai, T. (1994). Improvement of the rectal bioavailability of latamoxef sodium by adjuvants following administration of a suppository. Biological and Pharmaceutical Bulletin 17, 1496–500.[Medline]

17 . Van Hoogdalem, E. J., Geerts, J. A. M., De Boer, A. G. & Breimer, D. D. (1988). The influence of components on the rectal absorption of cefazolin in rats. Journal of Pharmacy and Pharmacology 40, 815–7.[ISI][Medline]

18 . Van Hoogdalem, E. J., Wackwitz, A. T. E., De Boer, A. & Breimer, D. D. (1989). 3-Amino-1-hydroxypropylidene-1,1-diphosphonate (APD): a novel enhancer of rectal cefoxitin absorption in rats. Journal of Pharmacy and Pharmacology 41, 339–41.[ISI][Medline]

19 . Unowsky, J., Behl, C. R., Beskid, G., Sattler, J., Halpern, J. & Cleeland, R. (1988). Effect of medium chain glycerides on enteral and rectal absorption of ß-lactam and aminoglycoside antibiotics.Chemotherapy 34, 272–6.[ISI][Medline]

20 . Briedigkeit, W., Gü6res, E., Schneeweiss, B., Wachholz, E. & Wiegand, U. (1972). Zur Problematik einer rektalen Chloramphenikol-Applikation. Pädiatrie und Grenzgebiete 11, 241–51.

21 . Farouk, A., Regdon, G., Mallalatif, G. & Abdel Hadi, I. A. (1984). Comparative study on ampicillin bioavailability from capsule and suppositories. Acta Pharmaceutica Hungarica 54,193 –9.[Medline]

22 . Sjü6vall, J., Westerlund, D., Alvan, G., Magni, L., Nord, C. E. & Sü6rstad, J. (1984). Rectal bioavailability of bacampicillin hydrochloride in man as determined by reversed-phase liquid chromatography. Chemotherapy 30, 137–47.[ISI][Medline]

23 . Bergstrü6m, B. K. V., Bertilson, S. O. & Movin, G. (1988). Clinical evaluation of rectally administered ampicillin in acute otitis media.Journal of International Medical Research 16,376 –85.[ISI][Medline]

24 . Davis, S. S., Burnham, W. R., Wilson, P. & O'Brien, J. (1985). Use of adjuvants for enhancement of rectal absorption of cefoxitin in humans. Antimicrobial Agents and Chemotherapy 28, 211–5.[ISI][Medline]

25 . Van Hoogdalem, E. J., Wackwitz, A. T. E., De Boer, A. G., Cohen, A. F. & Breimer, D. D. (1989). Rate-controlled rectal absorption enhancement of cefoxitin by co-administration of sodium salicylate or sodium octanoate in healthy volunteers.British Journal of Clinical Pharmacology 27, 75–81.[ISI][Medline]

26 . Pozzi, E., Luisetti, M. & Coppi, G. (1983). Sputum levels of erythromycin after rectal administration in adult patients with bronchitis. Current Therapeutic Research 33, 681–5.[ISI]

27 . de la Pierre, L., Acerbi, L., Gargantini, G., Manzoni, D. & Coppi, G. (1984). Livelli sierici di eritromicina dopo somministrazione rettale nella pratica pediatrica. Giornale Italiano di Chemioterapia 31, 229–32.[Medline]

28 . Acerbi, L., De La Pierre, L., Perietti, L. & Coppi,G. (1983). Bioavailability studies of erythromycin administered by rectal route in paediatric patients. Chemoterapia 2, 200–2.

29 . Stratchunsky, L. S., Nazarov, A. D., Firsov, A. A. & Petrachenkova, N. A. (1991). Age dependence of erythromycin rectal bioavailability in children. European Journal of Drug Metabolism and Pharmacokinetics Spec. No. 3, 321–3.

30 . Luke, D. R., Foulds, G., Going, P. C., Melnik, G. & Lawrence, V. (1997). Rectal azithromycin in healthy subjects. In Expanding Indications of the New Macrolides, Azalides and Streptogramins (Zinner, S. H., Lowell, L. S., Acar, J. F. & Neu, H. D., Eds), pp. 474–7. Marcel Dekker, New York.

31 . Bergan, T. & Arnold, E. (1980). Pharmacokinetics of metronidazole in healthy adult volunteers after tablets and suppositories. Chemotherapy 26, 231– 41.[ISI][Medline]

32 . Mattila, J., Männisto, P. T., Mätyla, R., Nykänen, S. & Lamminsivu, U. (1983).Comparative pharmacokinetics of metronidazole and tinidazole as influenced by administration route. Antimicrobial Agents and Chemotherapy 23, 721– 5.[ISI][Medline]

33 . Liedtke, R. and Haase, W. (1979). Steady-state pharmacokinetics of sulfamethoxazole and trimethoprim in man after rectal application. Arzneimittel-Forschung 29, 345–9.[Medline]

34 . Abd Ej-Gawad, A. H., Ramadan, E. & Nouh, A. T. (1988). Formulation and evaluation of trimethoprim–sulfamethoxazole suppositories. Pharmaceutical Industry 50,257 –60.

35 . Wagner, J. G., Carter, C. H. & Martens, I. J. (1968). Serum concentrations after rectal administration of lincomycin hydrochloride. Journal of Clinical Pharmacology and the Journal of New Drugs 8,154 –63.[Medline]

36 . Wagner, J. G., Leslie, L. G. & Gove, R. S. (1969). Relative absorption of both tetracycline and penicillin G administered rectally and orally in aqueous solution. Zeitschrift füCr Klinische Pharmakologie, Therapie und Toxikolgie 2, 44–51.

37 . Pfaff, G., Zimmermann, T., Lach, P., Yeates, R., Simon, G. & Wildfeuer, A. (1993). Pharmacokinetics and tolerance of fluconazole suppositories in healthy volunteers. Arzneimittel-Forschung 43, 391–5.[Medline]

38 . Joannides, L., Somogyi, A., Spicer, J., Heinzon, B., Tong, N., Franklin, C. et al. (1981). Rectal administration of metronidazole provides therapeutic plasma levels in postoperative patients. New England Journal of Medicine 305, 1569–70.[ISI][Medline]

Received 9 December 1996; returned 5 March 1997; revised 6 July 1998; accepted 4 September 1998





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