Significant reduction in chloroquine bioavailablity following coadministration with the Sudanese beverages Aradaib, Karkadi and Lemon
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1 Journal of Antimicrobial Chemotherapy (1994) 33, Significant reduction in chloroquine bioavailablity following coadministration with the Sudanese beverages Aradaib, Karkadi and Lemon B. M. Mahmoud', H. M. Ali', M. M. A. Homeida' and J. L. Bennetf "Department of Pharmacology, Faculty of Pharmacy and Vice Chancellor's Office, University of Khartoum, P.O. Box 1996, Khartoum Sudan; b Department of Pharmacology and Toxicology, Life Sciences, Michigan State University, E. Lansing, MI 48824, USA Chloroquine bioavailability in healthy males was examined following oral coadministration of 600 mg with three common Sudanese beverages, Aradaib (Tamarindus indicd), Karkadi {Hibiscus sabdarifa) and Lemon (Citrus limetta) and drinking water. The tablets and beverages were taken on an empty stomach after an overnight fast. The plasma chloroquine concentrations were measured by HPLC. The extent and rate of chloroquine bioavailability were described by the area under the plasma concentrations versus time curve (AUC), the peak plasma concentration (C^J and with the time to reach C^ (T^, respectively. The mean (±S.E.) AUC values after administration with water (control) and Aradaib, Karkadi and Lemon, respectively, were 7-52±0-87, 2-60±0-24, 216±0-30 and 2-41 ±0-29mg.h/L. The corresponding mean C^ values were 553 ±17-8, 184 ±21-3, 148 ±141 and 210 ± 17 4 mg/l and the corresponding I M values were 30±10, 3-2±1-2, 2-6±0-8 and 2-5±1 Oh. The results indicate a statistically significant reduction in the AUC and C amx of chloroquine as a result of a coadministration with each of the three beverages. A parallel reduction in the drugs antimalarial efficacy might be expected. Introduction Food and drink have long been recognised to affect many drugs pharmacokinetic (disposition and metabolism) and pharmacodynamic properties (Ali & Farouk, 1980; Wellin, 1980; Ali, 1981, 1982; Ali et ai, 1984; Vesel, 1984; Milton et al., 1989; Mandour, 1990). Dietary factors could affect drug disposition at several stages, including absorption, distribution, excretion and metabolism. The pharmacokinetic and clinical implications of these interations have recently received attention (Welling, 1977; Melander, 1978; Mandour et al., 1990). We have examined the effects of coadministration of the experimental antibiliharzial drug, oltipraz (Ali et al., 1984) and ampicillin (Ali & Farouk, 1980) with food. McLean et al. (1981) and Elvin et al. (1981) reported increased plasma concentrations of propanolol and Hgnocaine (lidocaine). Similarly serum concentrations of the antibilharzial drug, praziquantel were reduced by carbohydrate diets (Mandour et al., 1990). The bioavailability of the antimalarial drug, halofantrine was, however, increased by food (Milton et al., 1989). Chloroquine is the drug of choice for treatment of malaria in Sudan, and it has been common practice to take the drug with local beverages, particularly Citrus limetta /94/ J02.00/ The British Society for Antimicrobial Chemotherapy
2 1006 B. M. Mabmond et al. (Lemon), Hibiscus sabdarifa (Karkadi) and Tamarindus indica (Aradaib) squashes. Consequently we felt it was of importance to investigate the interactions of chloroquine with these drinks. Materials and methods Chloroquine diphosphate (250 mg tablets), Batch No. R2 5707, FR72J were purchased from Bayer, Leverkusen, Germany. Aradaib, Karkadi, and Lemon drinks were purchased locally. Chloroquine laboratory reference material was kindly supplied by Sterling Products, Khartoum, Sudan. The beverages were freshly prepared in such a way as to be similar in taste and concentration to those habitually consumed by the Sudanese people. The ph of each beverage was recorded, and was kept constant throughout the study. Six healthy male Sudanese adults of the same ethnic origin participated in the trial. They weighed kg (mean 56-6 ±8-5 kg), and were aged years (mean 23-9 ± 1-2). The trial was of a cross-over design with a 4-week wash out period. After overnight fasting each subject received four chloroquine tablets as a single dose equivalent to 600 mg base together with 300 ml of drinking water (control), or the beverages under investigation. Blood samples (5 ml) were collected from the cephalic vein using a catheter-butterfly system at 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12 and 24 h post dosing. Plasma was separated about 1 h after bleeding by centrifugation (1000#) at 25 C for 10 min to ensure complete separation (Rombo et al., 1985) and then stored at -20 C. Chloroquine plasma concentrations were determined by HPLC (Bergquist & Frisk-Holmberg, 1980). Intra- and inter-assay coefficients of variation were typically 6% and independent of concentration. The minimum detection limit was 5mg/L of chloroquine. Chloroquine bioavailability assessment Plasma chloroquine concentration versus time data, total dose administered and the body weight of each volunteer, were analysed to obtain the area under the plasma concentration versus time curve (AUC) using the PCNOLIN program run on a PC. Peak plasma concentrations (C^J together with the time to reach C^ (T^) were used to describe the extent and rate of bioavailability, respectively (Ritschel, 1976). Statistical significance was determined using Student's paired t-test. Results and discussion The AUC, C^ and T mmx values are summarised in the Table. There was a statistically significant difference between the AUC and C^ values for the control and the three beverage groups. There was however no difference between any groups with respect to T'mjm- The mean concentration versus time profiles are illustrated in the Figure. The C mmx values obtained were significantly lower than the control C,^ values although the mean T mmx values were comparable between all the groups. The AUC for the control group was about three times that for the test groups. Similarly the mean C mmx value for the control was also about three times that for the test groups. Thus coadministration of chloroquine with Aradaib, Karkadi or Lemon drinks causes a
3 Sudanese beverages and chloroqulnine bioavailability 1007 Time (h) Figure. Chloroquine plasma concentration versus time curves following oral administration of 600 mg base in single doses with the water (A) and the Sudanese beverages, Aradaib (O), Kardadi ( ) and Lemon ( ) to healthy adult male volunteers. significant reduction in drug bioavailability and consequently chloroquine antimalarial efficacy might be impaired. The therapeutic level of chloroquine for Plasmodium falciparum is 30^g/L (Adelusi et at., 1982) which is lower than the values obtained in this study. However, in malaria treatment with chloroquine the loading dose of the drug is crucial in the clearance of P. falciparum the most common parasite in the Sudan. We used 600 mg chloroquine base which was equivalent to the loading dose usually used, and with this dose we achieve serum concentrations that are higher than the therapeutic level to ensure rapid clearance of the parasite. For this reason we have predicted a reduction in the efficacy of the drug when taken with these acidic beverages. The significant reduction in chloroquine AUC and C mmx following concurrent administration of the drug with Aradaib, Karkadi or Lemon could be explained in terms of decreased absorption and increased renal excretion as a result of the enhanced acidity produced by the three beverages (ph The acidity of the tested beverages can be attributed to ascorbic, tartaric, hibiscus malis and oxalic acids (Ibrahim et al., 1971; Boutros, 1986). An increase in gut acidity would lead to greater ionization of the basic drug chloroquine and hence reduce absorption. The reverse is true in the renal Table. Chloroquine pharmacokinetics mean (±S.E.) values for six healthy male volunteers following oral administration of 600 mg base in single doses with the water and the Sudanese beverages, Aradaib, Kardadi and Lemon Parameter water (7-4) Beverage Aradaib (2-8) (ph) Karkadi (2-7) Lemon (2-6) AUC (mg.h./l) C (mg/l) T m Qi) 7-52 ± ± ± ±0-24" 184±21-3* 3-2 ±1-2' 216 ± ±14-1* 2-6 ±0-8' 2-41 ±0-20" 210±17-4* 2-5±l-0 f V = »P = 005. 'P = 0-05.
4 1008 B. M. Mahmond et al. tubules where the acidification of urine would reduce chloroquine reabsorption and accordingly increases excretion in urine. The effects of enhanced acidity in the gut and renal tubules produced by the beverages, would augment each other with respect to the reduction of chloroquine bioavailability. In some parts of rural Sudan people believe that Aradaib alone is a treatment for malaria and consequently they combine chloroquine tablets with Aradaib thinking that the drug and Aradaib will potentiate each other's antimalarial efficacy. These results are not in agreement with others. Tulpule & Krishnasway (1982) and Lagrave et al. (1985) reported enhanced chloroquine levels after coadministration with food. The enhancement of chloroquine absorption with food could be due to an increase of splanchnic blood flow and/or delay of the gastric emptying time (Bates et al., 1974). Bioavailability of all basic drugs (pka > 85) might be expected to be reduced as a result of a similar interaction with the tested beverages. It is therefore necessary when prescribing chloroquine or other related weakly basic analogues as well as other drugs, to advise the patients not to take the tablets with these beverages. Acknowledgements This work was supported by the US NIH/Sudan MRC Medical Parasitology Project, US NIH grant No. Al and the Sudan Medical Research Council. References Ali, H. M. (1981). The effect of Sudanese food and chloroquine on the bioavailability of ampicillin tablets. International Journal of Pharmaceutics 9, Ali, H. M. (1982). Prediction of food-drug interactions. Pharmacy International 3, 102. Ali, H. M. & Farouk, A. M. (1980). The effect of Sudanese diet on the bioavailability of ampicillin. International Journal of Pharmaceutics 6, Ali, H. M., Homeida, M. M. A., Sulaiman, S. M. & Bennett, J. L. (1984). Diet-controlled blood levels of oltipraz in healthy male subjects. Journal of Antimicrobial Chemotherapy 13, Bates, T. R., Sequeira, J. A., & Tembo, A. V. (1974). Effect of food on nitrofurantoin absorption. Clinical Pharmacology and Therapeutics 16, Bergqvist, Y. & Frisk-Holmberg, M. (1980). Sensitive method for the determination of chloroquine and its metabolite desethyl-chloroquine in human plasma and urine by high performance liquid chromatography. Journal of Chromatography 221, Boutros, J. Z. (1988). Sudan Food Composition Tables, 2nd edn. National Chemical Laboratories, Ministry of Health, Khartoum. Elvin, A. T., Cole, D., Pieper, J. A., Rolbin, S. H. & Lalka, D. (1981). Effect of food on lidocaine kinetics: mechanism of food-related alteration in high intrinsic clearance drug elimination. Clinical Pharmacology and Therapeutics 30, Ibrahim, M. E. H., Karamalla, K. A. & Khattab, A. G. (1971). Biochemical studies on Karkadi (roselle) (Hibiscus sabdariffa). Journal of Food Science and Technology 3, Lagrave, M., Stahel, E. & Betschart, B. (1985). The influence of various types of breakfast on chloroquine levels. Transactions of the Royal Society of Tropical Medicine and Hygiene 19, 559. Mandour, M. E. M., el Turatti, H., Homeida, M. M. A., el Sadig, T., Ali, H. M., Bennett, J. L. et al. (1990). Pharmacokinetics of praziquantel in healthy volunteers and patients until schistosomiasis. Transactions of the Royal Society of Tropical Medicine and Hygiene 84, McLean, A. J., Ibister, C, Bobik, A. & Dudley, F. J. (1981). Reduction of first-pass hepatic clearance of propanol by food. Clinical Pharmacology and Therapeutics 30, 31-4.
5 Sudanese beverages and chloroquinine bioavailability 1009 Melander, A. (1978). Influence of food on the bioavailability of drugs. Clinical Pharmacokinetics 3, Milton, K. A., Edwards, G., Ward, S. A., Ormer, M. L. E. & Breckenridge, A. M. (1989). Pharmacokinetics of halofantrine in man: effects of food and dose rise. British Journal of Clinical Pharmacology 28, Ritschel, W. A. (1976). Handbook of Basic Pharmacokinetics, 2nd edn, pp Drug Intelligence Publications, Hamilton. Rombo, L., Ericcson, O., Alvan, G., Lindstrom, B., Sjoqvist, F. & Gustafssom, L. L. (1985). Chloroquine and desthylchloroquine in plasma, serum, and whole blood: problems in assay and handling of samples. Therapeutic Drug Monitoring 7, Tulpule, A. & Krishnaswamy, K. (1982). Effect of food in bioavailability of chloroquine. European Journal of Clinical Pharmacology 23, Welling, P. G. (1977). Influence of food and diet on gastric-intestinal drug absorption review. Journal of Pharmacokinetics and Biopharmaceutics 5, Welling, P. G. (1980). Effect of food on bioavailability of drugs. Pharmacy International 1, {Received 27 August 1992; revised version accepted 16 July 1993)
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