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EFFECT OF FIVE ALIVE® FRUIT JUICE ON THE DISSOLUTION AND ABSORPTION PROFILES OF CIPROFLOXACIN *Akinleye M.O., Coker H.A.B., Chuckwuani C.M. and Adeoye A.W. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, College of Medicine, University of Lagos, Idi-araba, Lagos. *Corresponding author, e-mail address: [email protected] Key Words: Ciprofloxacin, Five Alive Citrus fruit and interaction 1 Abstract Objective: To determine the effect of interaction of five alive fruit juice® on the dissolution and absorption profiles of ciprofloxacin tablets using urinary excretion. Methods: In-vitro dissolution of ciprofloxacin 500mg tablets was studied using US Pharmacopoeia dissolution apparatus II. This was conducted using 0.1N HCl and equal volumes of the fruit juice and 0.1N HCL. Samples were collected at predetermined time intervals for two hours. For the in-vivo study, eleven (5 males and 6 females) healthy volunteers participated in an open, single dose, cross-over randomized trial. After an overnight fasting, each volunteer either ingested a 500mg ciprofloxacin tablet with 250ml table water or with the fruit juice. Total urine voided was collected for 72hrs after each dose of ciprofloxacin. Dissolution and urine samples were assayed using a controlled and validated UV spectrophotometric analysis. Results: A lag time of 5 minutes was observed in dissolution profile of ciprofloxacin in the juice. The percent dissolved of ciprofloxacin in 0.1NHCl and fruit juice were found to be dissimilar (f2 =18.2) using similarity factor. There was statistical difference between the Kel(elimination constant), Ke(excretion rate) and Xu (cumulative amount excreted unchanged) of subjects on water (0.1759±0.0144; 12.81±1.36; 375.5±41.2) and that of fruit juice (0.1250±0.0161; 7.6±1.07; 241.6±34.0). However, there was no difference between the ti/2 of the subjects (4.2±0.3; 5.5±0.8). There was a decrease in relative availability of the drug by 35.75%. Conclusion: We conclude that the absorption of ciprofloxacin can be reduced by concomitant ingestion of the juice containing calcium carbonate and grape. Therefore to avoid drug therapeutic failures and subsequent bacterial resistance as a result of subtherapeutic level of the drug in the systemic circulation, ingestion of the juice with ciprofloxacin should be discouraged. 2 INTRODUCTION Ciprofloxacin is a fluoroquinolones with a broad spectrum antibacterial activity. It has become one of the most commonly prescribed drugs for the treatment of a plethora of bacterial infections including pseudomonas aeruginosa, Neisseria spp and staphylococci. It has also been found useful in the treatment of enteric fever, fever of unknown origin (FUO) including anthrax treatment during biologic warfare 1. It is rapidly and well absorbed from the gastrointestinal tract, widely distributed in the body with good tissue penetration2 . Since its introduction into clinical practice, several pharmacokinetic and pharmacodynamic interactions have been reported 3. Polyvalent cations such as aluminium, calcium, copper, iron, magnesium, manganese and zinc found in dairy products (milk, cheese, and yogurt), antacids and mineral supplements can bind ciprofloxacin, greatly reducing the absorption of the drug 4. Calcium supplements are known to interfere with the absorption of ciprofloxacin. The same interaction has been shown to occur when calcium-fortified orange juice is taken at the same time as ciprofloxacin 5. The general mechanism by which the interactions occur has been through formation of insoluble metallic ion complex with ciprofloxacin. Ciprofloxacin has also been reported to increase serum concentrations of some drugs that are substrates of cytochrome P450 1A2 and 3A4 by inhibition of these metabolic enzymes 6. Grape juice also interacts with several drugs particularly those that are substrates of cytochrome P450 3A4 e.g. dihydropyrines (nifedipine 7,felodipine 8), cyclosporine 9,midazolam 10 etc. This isoenzyme is found in the liver and in the enterocytes. Some drugs are thus metabolized as they are absorbed by the enterocytes. Drugs can also be 3 pumped back into the intestinal lumen from the gut wall by a P-glycoprotein transporter (P-gp). P-gp and CYP3A4 may therefore act in tandem as a barrier to drugs moving from the gut to the systemic circulation 11. Grape juice appears to selectively inhibit intestinal CYP3A4 isoenzyme expression 12. Inhibition of either or both systems can increase the bioavailability of a drug. Majority of clinically relevant food-drug or drug-drug interactions are caused by food/drug-induced changes in the bioavailability of the drug. Since the bioavailability and clinical effect of most drugs are correlated 13, the bioavailability is then an important pharmacokinetic parameter. However, in order to evaluate the clinical relevance of a food-drug interaction, the impact of food intake on the pharmacokinetic and clinical effects of the drug has to be quantified. It is common place for patients to take drugs with drinks other than water for various reasons, one of which is to mask the unpleasant taste already associated with some drugs and secondly, fruit juice is often part of the menu for breakfast in some homes when medications are taken. Moreover it’s also being used to administer drugs to children for better compliance. Some of these drinks include fruit juice, milk, beverages and yogurt. It is not impossible that ciprofloxacin can auto inhibit these enzymes (cytochrome P450 3A4 & 1A2) and paves way for it entrance into the systemic circulation, we therefore hypothesized that there may be a relevant interaction between grape juice; calcium content of the juice and the drug. Of what effect is the presence of these counteracting components to the pharmacokinetics of ciprofloxacin? This study was therefore carried out to determine if the in vitro dissolution release and systemic availability of ciprofloxacin would be altered when administered with Five alive® citrus fruit juice which contains among others, grape juice and fortified with calcium. 4 MATERIALS AND METHODS Drugs, Chemicals and Equipment Ciprofloxacin standard (Fig. 1) was provided by Fidson Health Care Nigeria Limited while ciprofloxacin (Ciprotab®) tablets were purchased from a registered pharmaceutical chemist. 0.1N Hydrochloric acid (HCl) and deionized water were obtained from Swiss Pharma Nigeria limited. Sontax AT 7 vessel dissolution apparatus USP II (Bassel, Switzerland) and Agilent 8453 UV/Visible system with ChemStation software coupled with Hp Computer system; universal paper pH indicator were used. Five Alive® Citrus Burst fruit Juice(FACBF) (Batch ADJ5107, Reg. 01-5715) and Eva® table water, products of Nigerian Bottling Company under license and authority of Coca-cola Company, Nigeria were procured from registered premises. The FACBF contains 43% Lemon, Orange, Lime, Grape juice, tangerine; calcium phosphate, calcium Lactate (120mg/100ml) with no flavours, colours or preservative. IN-VITRO STUDY Pre-sample tablets analysis was done by evaluating two physicochemical characteristics vis-à-vis disintegration test and assay in order to ascertain the suitability of the ciprofloxacin tablets for the studies according to the official specifications. Dissolution Testing A 7-compartment dissolution US Pharmacopoeia apparatus II was maintained at 37± 0.5oC with a degree of agitation of 50revolution/minute and 900ml of dissolution medium per vessel was used. The dissolution experiment was conducted in two phases; one involved the dissolution of 500mg ciprofloxacin tablet using 0.1NHCl as dissolution medium while the other contained equal 450mls of 0.1N HCl and FACBF juice. Sample (2.0ml) was collected at pre-determined time intervals (5, 10, 20, 30, 5 40, 50, 60, 80 and 120minute). 0.1ml of the sample diluted to 10mls with 0.1NHCl was filtered with 0.45µm Millipore filter and assayed by UV spectrophotometric method at a wavelength of 277nm. Graph of absorbance versus concentration was plotted for the ciprofloxacin standard solutions, thus the concentration of each sample was determined using the equation of the calibration. Provision was made in the calculation for each sample volume taken without replacement. IN-VIVO STUDY The study was a randomized, open and cross-over study design in two phases of an interval of one week wash-out period. Written consent was obtained from 12 volunteers (6 men, 6 women) aged from 21 to 41 years (mean age, 27.4± 7.9 years) with a mean weight of 63.3±5.6 kg (ranged 57 – 78kg) were enlisted into the study. The study was approved by Research and Ethics Committee, Lagos University Teaching Hospital (LUTH). Volunteers were excluded from the study if they had any known gastrointestinal problem, such as peptic ulcer disease, colitis, nausea, vomiting, and diarrhea or malabsorption syndromes. No alcohol or citrus fruits or juices were to be ingested in any form three days pre-treatment day. Volunteers who were taking any drug or had a history of hypersensitivity to quinolones and fruit juices were also excluded from the study. After the subjects fasted overnight, each volunteer then swallowed a single 500mg tablet of ciprofloxacin (as the hydrochloride salt) with 250ml of either water or FABCF juice simultaneously at 0900. Zero hour urine was collected. In order to promote adequate urine flow during the 12 hours of the first day, the subjects were allowed to take water but debarred from taking breakfast the morning of the study until four hour post drug administration. The total urine voided was collected, the pH and volume measured and 6 recorded. 20ml aliquots of the urine was taken and stored in refrigerator at 0 to -100C until analyzed Analysis of urine samples A known concentration (10µg/ml) of CP standard was prepared in O.1N HCl and scanned in UV spectrophotometer to obtain the λmax of absorption of the drug. Ciprofloxacin stock (5-60µl) solution of 5mg/ml was spiked in 1ml of blank urine to give a concentration range of 25-350µg/ml. 0.4ml of concentrations (25-350µg/ml) was further diluted to 10ml with 0.1N HCl to give a concentration range of 1-12µg/ml for the calibration standard plot (n in triplicate). The regression coefficient, r2 of the calibrator was determined prior to analysis of the samples. For the first 24hr urine samples, I in 250 dilutions in 0.1N HCl was used while 48-72hrs samples were diluted 25 times. Individual zero hour urine was used as blank for analysis of CP in subject samples. On the spot % recovery was evaluated by comparing the absorbance of CP spiked in urine with that prepared in 0.1N HCL using UV spectrophotometer at the scanned wavelength 277nm. Data Analysis The concentrations of CP measured in urine were multiplied by the respective urinary volume to obtain the amount excreted in the sampling time. The dilution of the samples was taken into account for calculation of the drug concentration. The rate plot (urinary excretion rate plot versus time) for both CP in juice and water did not yield a straight line rather the resulting curve was biexponential. The elimination rate constant (Kel) was calculated by regression of the terminal portion of the log-linear excretion rate-mid time curve. The ti/2 of elimination was the evaluated from expression 0.693/Kel. The 7 cumulative amount excreted up to 72hrs time (Xu) was obtained by summing the amount excreted unchanged in each time interval up to that time. The excretion rate constants (Ke) and Xu were also evaluated using the Microsoft Excel Tools. Statistical Analysis Kel, t1/2, Ke were compared by student’s t test of subjects taking ciprofloxacin with water and FABCF juice. In all cases, a confidence level of 95% (α = 0.05) was chosen for all statistical test and a value of p≤0.05 was considered significant. Graph pad prism version 4.0 software program and Microsoft Excel Analytical Tools were applied. The dissolution data were also analyzed by estimation of similarity factor, f2 using dissolution time points (5 to 40mins) in 0.1N HCl as reference and presented in the following equation. F2 = 50log{[1 + 1/n∑(Rt – Tt)2]-0.5 x 100} where Rt and Tt are percent dissolved at each time point for reference and test respectively. Using the f2 values, dissolution profiles were considered dissimilar if these values were less than 50 14,15. RESULTS The assay and average disintegration time were found to be 104.5 ± 1.2% and 3.0 ± 0.1 minutes respectively. The percent ciprofloxacin released from dissolution in 0.1N HCl and fruit juice was presented in Fig.II. The results of mathematical comparison of dissolution time points profile in water and the juice using similarity factor, f2 was found to be 18.8. Eleven subjects, 21-42 years of age (mean ± SD., 27.2 ± 8.2 years) with a mean weight of 63.6 ± 5.7 (ranged 57-78kg) completed the study. Figure IIIa & b represent the UV spectra of blank urine and spiked drug standard (1-12µg/ml) in urine at λmax wavelength 277nm. There was an average % recovery of 88.9 ± 11.8 of CP in 8 urine compared to the drug in 0.1N HCl solution at 5 different concentrations. Fig. IIIc represents the overlaid sample spectra for two subjects. The mean biexponentials curves of Log excretion rate versus the sampling time of subjects using water and juice are represented in Figure IV. Figure V represents average cumulative amount of unchanged CP excreted Plots versus mid-time of both subjects (water/juice). The statistical student’s t test parametric comparison of urinary excretion date of the drug taken with water versus juice following oral administration are shown in Table I . There were significant level of difference between the two treatment in Kel. Ke and Xu while no significant difference was obtained in elimination t1/2 . The bioavailability of CP given concurrently with the juice relative to that administered with table water was 0.64. DISCUSSION Pre-sample assay of the ciprofloxacin tablets showed conformity with official stipulation in the BP 1998 16. The tablets were found to disintegrate at average time of 3.0± 0.1 minutes which also fell within the official limit. The similarity factor, f2 (18.2) confirms dissimilarity between the dissolution of ciprofloxacin in 0.1N HCl and FACBF juice. The absolute reduction of ciprofloxacin release in the fruit juice at 5minutes as shown by the lag phase (Fig. II) might be an indication of complexation between the drug and the calcium ions in the fruit juice. The manufacturer’s label claim of the Five Alive® citrus fruit juice shows calcium content of 120mg/100ml while the five fruits (lemon, orange, and lime, tangerine and grape fruit) constitute 43% of the total juice contents. Out of these ingredients, 9 calcium compounds have been reported 17,18 and extensively implicated in the interaction with ciprofloxacin both in-vitro and in-vivo. A mean reduction of 30 - 40% in Cmax and 30 - 51% in plasma AUC and urinary excretion has been reported 19,20,21. We observed 35.75% reduction in relative availability of the drug in juice. This finding is in congruence with the earlier reports but however our result could not ascertain if any contrary effect was contributed by the grape fruit content of the juice. It could well mean that the calcium carbonate complexation effect overrides the possible grape fruit inhibition of intestinal enzyme (CytoP4503A4) as reported with some drugs such as Felodipine, Nifedipine etc. Perhaps, the enzyme inhibition effect may be infinitesimal. It was also noticed in one of the subject where there was over 90% inhibition of the drug excreted in the urine using the juice. There was no gender difference in all the urinary parameters derived except in excretion rate where the rate tends to be faster in females than the males using the juice to swallow the drug and this was found to be statistically significant (p≤ 0.006). We also found out that the rate of absorption in water juice is faster than that of the juice which explained the decrease in availability of ciprofloxacin in FACBF juice. Brittan et al. 22, reported a t1/2 of 4.14 hr on oral single dose of 500mg ciprofloxacin when used with water while t1/2 of 4.2±0.3hr was got in this study. By way of conclusion, we have confirmed that concomitant administration of ciprofloxacin in the presence of calcium carbonate and grape fruit in Five Alive® juice still lead to reduction of bioavailability. The phenomenal increase in bioavailability of drug co-administered with grape fruit was not noticed. Therefore, the incessant habit of swallowing drug with fluids other than water should be done with great caution. 10 Acknowledgment We wish to appreciate the management and staff of Swiss Pharma Nigeria Limited for making their laboratory space and equipment available for the study. REFERENCES [1]. CDC Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines MMWR 2001; 50: 889-97. [2]. Neuman M. Clinical pharmacokinetics of the newer antibacterial 4-quinolones. Clin Pharmacokinet 1988; 14: 96-121. [3]. Davey PG. Overview of drug interactions with the quinolones. J Antimicrob Chemother 1988; 22 (suppl.c): 97-107. [4]. Campbell NR, Hasinoff BB. A common cause of drug interactions. Br J Clin Pharmacol 1991; 31: 251-5. [5]. Neuhofel AL, Wilton JH, Victory JM. Lack of bioequivalence of ciprofloxacin when administered with calcium-fortified orange juice: a new twist on an old interaction. J Clin Pharmacol 2002; 42: 461-6. [6]. S. Raoof, C. Wollschager, F.A Khan, American Journal of Medicine 84 (suppl,4A) (1987) 115-118. [7]. Bailey DG, Spence JD, Munoz C, Amold JM. Interaction of citrus juices with felodipine and nifedipine. Lancet. 1991; 337: 268-9. [8]. Edgar B, Bailey D, Bergstrand R. Acute effects of drinking grape fruit juice on the pharmacokinetics and dynamics of felodipine and its potential clinical relevance. Eur J Clin. Pharmacol 1992; 42: 313-17. 11 [9]. Ducharme MP, Provenzano R, Dehoorne-Smith, Edwards DJ. Trough concentrations of cyclosporine in blood following administration with grape fruit juice. Br J Clin Pharmacol 1993; 36: 457-59. [10]. Hugo HT, Kupfer S, HuyRiem H, Walter HZ, Peter JM. Interaction between grape juice and midazolam in humans. Clin Pharmacol Ther 1995; 58: 20-28. [11]. McNeece J. Grape fruit juice interactions. Austr Prescr 2002 ; 25 : 37 [12]. Bailey DG, Malcolm J, Arnold O, Spencer JD. Grape fruit juice-drug interactions. Br J Clin Pharmacol 1998; 46: 101-10. [13]. Schmidt LE, Dalhoff K. Food-drug interactions. Drugs 1998; 62(10): 1481- 505. [14]. Moore JW, Flanner HH. Mathematical comparison of curves with emphasis on dissolution profiles. Pharm. Tech. 1996; 6: 64-74. [15]. Thomas OH, Adrian D Jackie B John D. A review of methods used to compare dissolution data. PSTT 1998; 1(5): 214-223. [16]. British Pharmacopoeia Volume I & II. British Pharmacopoeia commission, stationery office limited, United Kingdom (1998) Pp 1451-2 & 1573. [17]. Sahai J, Healy DP, Stotka J, Polk RE. The influence of chronic administrationof calcium-carbonate on the bioavailability of oral ciprofloxacin. Br J Clin Pharmacol. 1993; 35(3): 302-4. [18]. Kato R, Ueno K, Imao H, Kawai M, .Kuwahara S. Impairment of ciprofloxacin absorption by calcium polycarbophil. J Clin Pharmacol. 2002; 42(7): 806-11. [19]. Neuvonen PJ, Kivisto KT, Lehto P. Interference of diary products with the absorption of ciprofloxacin. Clin Pharmacol Ther. 1991; 50(5pt 1): 498-502. [20]. Kays MB, Overholser BR, Mueller BA, Moe SM, Sowinski KM. Effects of sevelamer hydrochloride and calcium acetate on the oral bioavailability of ciprofloxacin. Am J Kidney Dis 2003; 42(6): 1253-9. 12 [21] Wagenlehner FM, Kinzig-Schippers M, Tischmeyer U, Wagenlehner C, Sorgel F, Dalhoff A, Naber KG. Int J Antimicrob Agents 27(1) (2006) 7-14 [22]. Brittain DC, Scully BE, McElrath MJ, Sternman R, Labthavikul P et al. J Clin Pharmacol 1985; 25: 82-88. 13 Table 1 Mean± SEM: Urinary Excretion Data of CP taken with Water versus Juice Parameter/ Treatment Unit Water Juice P-value N 11 11 t1/2 /hr 4.2±0.3 5.5±0.8 Kel /hr-1 0.1759±0.0144 0.1250±0.0161 * 0.046 Ke /mg/hr 12.81±1.36 7.60±1.07 * 0.007 Xu /mg 375.5±41.2 241.6±34.0 * 0.021 N = number of subject * = significant o = not significant Fig. 1: Structure of ciprofloxacin O COOH F N N N H 14 o 0.176 Fig. II: Dissolution profile of Ciprofloxacin (500mg) tablets in 0.1N HCl and Fruit juice as dissolution media 120 % ciprofloxacin released 100 80 60 40 CP500mg in 0.1NHCl 20 CP500mg in juice 0 0 20 40 60 80 -20 time/min Fig 3a The blank spectrum of urine 15 100 120 Fig. 3b: The processed standard spectra of CP spiked in urine Fig. 3c: Overlaid sample spectra of recovered CP in two of the subjects 16 Fig. 4 Mean ± SEM: Average Excretion rate (CP) versus mid-time in water and juice Excretion rate (CP),mg/hr 50 40 30 20 10 0 -10 0 20 40 60 mid-time/hr □ = water □= juice 17 80 Fig.5: Mean ± SEM. Cumulative amount of ciprofloxacin excreted unchanged when administered with water and fruit juice 450 400 350 X u/mg 300 250 200 water 150 100 juice 50 0 0 10 20 30 40 50 60 mid-time/hr 18 70 19