Effect of gum arabic on the absorption of a single oral dose of amoxicillin in healthy Sudanese volunteers

I. B. Eltayeb1, A. I. Awad2,*, M. A. Elderbi1 and S. A. Shadad1

1 Department of Pharmacology, Faculty of Pharmacy, University of Khartoum, PO Box 1996, Khartoum, Sudan; 2 Department of Pharmacy Practice, Faculty of Pharmacy, Kuwait University, PO Box 24923, Safat 13110, Kuwait

Keywords: pharmacokinetics , interactions , antibiotics , renal failure

Sir,

Gum arabic is defined as the dried gummy exudate from the stems and branches of Acacia Senegal, Willdenow or other related African species of Acacia (Leguminosae). It is a complex of very high molecular weight acidic heteropolysaccharides, which is widely used in pharmaceutical preparations as a suspending, demulcent, soothing and emulsifying agent. It was reported that gum arabic increased faecal nitrogen excretion, decreased urea production and decreased urea-nitrogen recycling.1 A study in animal models of experimental chronic renal failure showed that consumption of diets containing fermentable carbohydrates resulted in a greater faecal nitrogen excretion coupled with a reduction in serum urea concentration.2 In 1996, Bliss et al.3 reported that patients with chronic renal failure consuming a low-protein diet with 50 g gum arabic/day had a greater faecal nitrogen excretion and lower serum urea than patients consuming only a low-protein diet. Gum arabic is commonly prescribed for chronic renal failure in patients in Sudan; it results in decreased uraemia and reduces the frequency of dialysis, hence improving the quality of life. This study was conducted to investigate the effect of gum arabic on the absorption of amoxicillin, an antibiotic commonly prescribed for the treatment of urinary tract infections in patients with chronic renal failure.

The study design was open and randomized; 24 healthy adult volunteers were allocated into four groups, six in each group. They gave written consent. None of them had a history of hypersensitivity to penicillin. Ethical approval was obtained from the Sudanese Ethical Committee. In the control group (group I), a single oral dose of amoxicillin capsules 500 mg (SmithKline Beecham, Brentford, UK) was administered after 12 h overnight fasting; in the test groups the same dose of amoxicillin was given after 12 h overnight fasting as follows: concurrently with gum arabic (group II); 2 or 4 h after gum arabic ingestion (groups III and IV, respectively). Blood samples (5 mL) were taken at 0, 0.5, 1, 1.5, 2, 4 and 6 h after amoxicillin administration. The serum was separated and stored at –70°C until assay, which was within 1 week of collection.

Determination of amoxicillin concentrations in the serum samples was carried out by a validated cup-plate agar diffusion method using Staphylococcus aureus (ATCC 25923) as the test organism.4 The standard inoculum of the test organism was prepared as described by Cheesbrough.5 The standard amoxicillin concentrations (0.25–8 mg/L) were prepared under aseptic conditions. All samples were assayed in quadruplicate in pooled human serum, and all the samples from each adult were analysed in parallel. The log of the known concentrations of amoxicillin standards was plotted against the mean inhibition zone diameter; it was linear over the concentration range studied with r2 > 0.98. The within-day precision of replicate samples of 0.5 mg/L (n=6) and 5.0 mg/L (n=6) gave relative standard deviations of 2.5% and 1.1%. The day-to-day relative standard deviations for the standards 0.5 and 5 mg/L (n=6) were 3.2% and 1.2%, respectively. The assay detection limit in serum was 0.02 mg/L.

Determination of the maximum peak concentration of amoxicillin (Cmax) and the time it was attained (Tmax) were obtained by visual inspection of individual patient data. The calculation of the terminal elimination rate constant (kel), terminal half-life (t1/2) and area under the curve (AUC0–{infty}) was conducted according to a non-compartmental model using WinNonlin Professional 4.1 (Pharsight Corporation, Cray, NC, USA). Statistical analysis was carried out with SPSS for Windows Version 12. Mean pharmacokinetic data were compared at a statistical significance level of P<0.05 and 95% confidence interval.

The administration of amoxicillin concurrently with gum arabic (group II) and 2 h following the ingestion of gum arabic (group III) significantly decreased the Cmax from (mean ± S.D.) 7.31 ± 0.99 mg/L to 2.00 ± 0.67 mg/L and 3.19 ± 1.5 mg/L, respectively (Figure 1), and the AUC0–{infty} of amoxicillin from (mean ± S.D.) 21.34 ± 1.85 mg·h/L to 4.56 ± 1.45 mg·h/L and 10.97 ± 3.99 mg·h/L, respectively when compared with the control group (P < 0.05). In group IV, the Cmax and AUC0–{infty} were not significantly different from those in the control group. The Tmax was not significantly different in the four groups; it was (mean±S.D.) 2.00±0.00, 1.67±0.26, 1.75±0.27 and 1.83±0.41 h in groups I, II, III and IV, respectively. The kel and t1/2 of amoxicillin following oral administration were (mean ± S.D.) 0.54 ± 0.09 h–1 and 1.31 ± 0.27 h, 0.65 ± 0.13 h–1 and 1.11 ± 0.22 h, 0.47 ± 0.11 h–1 and 1.56 ± 0.43 h, and 0.48 ± 0.13 h–1 and 1.54 ± 0.42 h in groups I, II, III and IV, respectively. These were not significantly different (P > 0.05).



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Figure 1. Mean ± S.D. serum concentrations of amoxicillin following co-administration with gum arabic.

 
Gum arabic requires about 4 h from oral intake until it reaches the colon. This may explain the significant reduction in absorption of amoxicillin when administered concurrently or 2 h after gum arabic, but the lack of a significant difference in absorption when administered 4 h following the intake of gum arabic.

Our findings indicate that the coexistence of amoxicillin and gum arabic in the upper gastrointestinal tract resulted in a pharmacokinetic interaction that significantly decreased the absorption of amoxicillin. Sub-therapeutic plasma concentrations of amoxicillin may lead to therapeutic failure and may increase the likelihood of developing drug resistance. This may lead to clinical failure and will require new drug development, which will be more expensive and will further disadvantage patients in developing countries. We recommend that amoxicillin should be administered 4 h pre- or post-ingestion of gum arabic.

Acknowledgements

We would like to thank the students of Pharmacy—University of Khartoum who acted as volunteers in this study. We deeply thank the Drug Control and Research Directorate for the supply of standard drugs and microorganisms and the Kidney Dialysis Center—Khartoum for the supply of the gum arabic. Subject selection, screening and blood sampling, serum assay, data interpretation and writing were carried out at the University of Khartoum—Sudan and Kuwait University—Kuwait. The receipt of financial support from El-Shifa Pharmaceutical Co. is gratefully acknowledged. There are no potential conflicts of interest for any of the authors.

Footnotes

* Corresponding author. Tel: +965-6026009; Fax: +965-5342807; Email: amoneim{at}hsc.edu.kw

References

1 . Assimon, S. A. & Stein, T. P. (1994). Digestible fiber (gum arabic), nitrogen excretion and urea recycling in rats. Nutrition 10, 544–50.[ISI][Medline]

2 . Younes, H., Alphones, J. C., Behr, S. R. et al. (1999). Role of fermentable carbohydrate supplements with a low-protein diet in the course of chronic renal failure: experimental bases. American Journal of Kidney Diseases 33, 633–46.[ISI][Medline]

3 . Bliss, D. Z., Stein, T. P., Schleifer, C. R. et al. (1996). Supplementation with gum arabic fiber increases fecal nitrogen excretion and lowers serum urea nitrogen concentration in chronic renal failure patients consuming a low protein diet. American Journal of Clinical Nutrition 63, 392–8.[Abstract]

4 . British Pharmacopoeia, vol. 1 (1993), pp. 19–20. HMSO, London, UK.

5 . Cheesbrough, M. (1985). Antimicrobial sensitivity testing. In Medical Laboratory Manual for Tropical Countries, vol. 2: Microbiology, 1st edn, pp. 196–205. Tropical Health Technology and Butterworth-Heinemann Ltd, Oxford, UK.





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