Effect of magnesium trisilicate on nitrofurantoin absorption In vitro adsorption studies revealed that for an identical initial concentration of nitrofurantoin, magnesium trisilicate exhibited the greatest adsorptive capacity with bismuth oxycarbonate, talc, kaolin, and magnesium oxide exhibiting intermediate adsorptive powers, while aluminum hydroxide and calcium carbonate exhibited low or no adsorption properties. Trials to elute the drug with acidic or alkaline solution were unsuccessful. The in vivo absorption characteristics of nitr(Jj'urantoin and nitrofurantoin-magnesium trisilicate combination were evaluated in 6 healthy males. Administration ()f magnesium trisilicate with nitrofurantoin reduced the rate and extent of its excretion reflecting decrease in both rate and extent of absorption. The time during which the drug concentration in the urine was above the minimum effective concentration of 32 p.,g /ml was also significantly reduced after administration of the antacid.
Viviane F. Naggar, Ph.D., and Said A. Khalil, Ph.D. Alexandria, Egypt Department of Pharmaceutics, Faculty of Pharmacy, University of Alexandria
Nitrofurantoin is known to induce severe gastric distress, irritation of the mucosa, as well as systemic nausea and emesis. 18 It is sometimes recommended with food or milk to minimize the incidence of these side effects. 19 It is not uncommon that patients use antacid preparations to relieve its undesirable gastrointestinal symptoms. Such concurrent administration may reduce this induced gastric irritation but there may also be a change in the bioavailability of the nitrofurantoin. Hurwitz 5 recently reviewed drug-antacid interactions. In vitro studies provided evidence of interaction between commonly used antacids and anticholinergics, I, 10 tranquilizers,lo antibiotics,8 antirheumatics, 16 corticosteroids, 15 contraceptive steroids,9 digitalis glycosides,6 and Partially supported by the United States National Science Foundation under SFC Program Grants GF 39207 and GF 38851. Received for publication Sept. 1, 1978. Accepted for publication Jan. 16, 1979. Reprint requests to: Dr. Said A. Khalil, Department of Pharmaceutics, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
antiepileptics. 14 These antacid interactions may alter the gastrointestinal absorption of drugs. Magnesium trisilicate reduced the bioavailability of tetracycline, 7 dexamethasone, 17 or digoxin. 2 Aluminum hydroxide and aluminum hydroxide-magnesium carbonate-magnesium hydroxide combination were also reported to decrease the bioavailability of digoxin2 and indomethacin. 4 Our purpose was to determine whether there was a nitrofurantoin antacid interaction by means of an adsorption-elution test. The antacid interaction on the bioavailability of nitrofurantoin was tested in man. Materials and methods
Nitrofurantoin and nitrofurantoin tablets 100 mg (EI- Kahira) were used. The antacids were magnesium trisilicate, aluminum hydroxide, magnesium oxide, and calcium carbonate, all of B.P. grade. Bismuth oxycarbonate B.P.C., an ingredient commonly used with antacids, talc B.P., a common excipient in tablet formulations, kaolin and charcoal B.P., model adsor-
0009-9236/79/060857+07$00.70/0 © 1979 The C. V. Mosby Co.
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Naggar and Khalil
Clin. Pharmacol. Ther. June 1979
Table I. Percentage of nitrofurantoin adsorbed per gram adsorbent and percentage eluted* (initial concentration, 3.003 mgllOO ml) Adsorbent
pH of antacid suspension
Magnesium trisilicate Bismuth oxycarbonate Talc Charcoal Kaolin Aluminium hydroxide Magnesium oxide Calcium carbonate
7.6 2.6 2.4 4.0 2.3 6.5 8.1 7.7
Nitrofurantoin adsorbed (%)
99.3 (0.32; 5.58) 53.3 50.5 99.6(0.34; -) 31.7 2.5 26.8 0.00
'Figures in parentheses represent the percentage of the drug eluted using 0.01 N HCl or 0.014 N NaHCOa (second figure).
bents, the latter with a large hydrophobic surface, were also included for comparison. In vitro study. The procedure adopted in adsorption and elution has been reported. 15 The study was done in 0.01 N HCI (pH, 2.2) to simulate gastric pH conditions. Drug concentrations ranged from 0.3 to 6.6 mg/lOO m!. Eluting solutions were 0.01 N HCI and 0.014 N NaHC0 3 (pH, 7.4). In both adsorption and elution studies, nitrofurantoin (protected from light) was assayed spectrophotometric ally at 370 nm. In vivo study. The absorption characteristics of nitrofurantoin and nitrofurantoin-magnesium trisilicate combination were evaluated in 6 adult male volunteers with no known history of urinary tract diseases or hypersensitivity to nitrofurantoin. A crossover design was followed. The subjects were instructed not to take other medication or alcoholic beverage for 14 days prior to the study and through the entire test period. A single lOO-mg nitrofurantoin tablet was taken orally by each volunteer with 150 ml of water (treatment A) or with 150 ml water containing 5 gm magnesium trisilicate (treatment B) after an overnight fast of not less than 8 hr. At least 1 wk elapsed between the two treatments. Subjects were given a light lunch 4 hr after either treatment. No adverse experiences were reported by the subjects. Urine specimens were collected at predetermined time intervals over a 12-hr period; pH and volume were measured. Immediately prior to taking nitrofurantoin, a zero time urine specimen was collected. Drug concentration in the urine was determined by the modified 12 spectrophotomet-
ric method of Conklin and Hollifield3 specific for un metabolized nitrofurantoin. Appropriate urine blank corrections were made. All urine samples were stored in a cool place and protected from light. Results
The percentage nitrofurantoin adsorbed on the different antacids or adsorbents is shown in Table I. For an identical initial concentration of the drug, magnesium trisilicate and charcoal exhibited the greatest adsorption capacity. Bismuth oxycarbonate, talc, kaolin, and magnesium oxide had intermediate adsorption and aluminum hydroxide and calcium carbonate had little or no adsorptive property. Magnesium trisilicate suspension in 0.01 N HCI had a pH of about 7.6. At this pH, nitrofurantoin, a weak acid (pKa, 7.2), will be about half ionized. Depletion of nitrofurantoin from solution, in the presence of magnesium trisilicate, therefore may be due to adsorption on the antacid surface, partially through binding to electron-accepting sites. 13 Adsorption through simple van der Waal's attraction of the nonionized hydrophobic portion of nitrofurantoin is also suggested since charcoal (a model adsorbent with a large hydrophobic surface area and a relatively acidic suspension in 0.01 N HCI, pH 4) as well exhibited a high adsorption power for the drug. Nitrofurantoin-magnesium trisilicate interaction seems rather strong since attempts to elute the drug with solution of physiologic pH values (namely, 0.01 N HCI and 0.014 N NaHC0 3 ) were not successful (Table I). The adsorption isotherm for nitrofurantoin on mag-
Volume 25 Number 6
Magnesium trisilicate-nitroJurantoin interaction
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Viviane F. Naggar, Ph.D., and Said A. Khalil, Ph.D. Alexandria, Egypt Department of Pharmaceutics, Faculty of Pharmacy, University of Alexandria
Nitrofurantoin is known to induce severe gastric distress, irritation of the mucosa, as well as systemic nausea and emesis. 18 It is sometimes recommended with food or milk to minimize the incidence of these side effects. 19 It is not uncommon that patients use antacid preparations to relieve its undesirable gastrointestinal symptoms. Such concurrent administration may reduce this induced gastric irritation but there may also be a change in the bioavailability of the nitrofurantoin. Hurwitz 5 recently reviewed drug-antacid interactions. In vitro studies provided evidence of interaction between commonly used antacids and anticholinergics, I, 10 tranquilizers,lo antibiotics,8 antirheumatics, 16 corticosteroids, 15 contraceptive steroids,9 digitalis glycosides,6 and Partially supported by the United States National Science Foundation under SFC Program Grants GF 39207 and GF 38851. Received for publication Sept. 1, 1978. Accepted for publication Jan. 16, 1979. Reprint requests to: Dr. Said A. Khalil, Department of Pharmaceutics, Faculty of Pharmacy, University of Alexandria, Alexandria, Egypt.
antiepileptics. 14 These antacid interactions may alter the gastrointestinal absorption of drugs. Magnesium trisilicate reduced the bioavailability of tetracycline, 7 dexamethasone, 17 or digoxin. 2 Aluminum hydroxide and aluminum hydroxide-magnesium carbonate-magnesium hydroxide combination were also reported to decrease the bioavailability of digoxin2 and indomethacin. 4 Our purpose was to determine whether there was a nitrofurantoin antacid interaction by means of an adsorption-elution test. The antacid interaction on the bioavailability of nitrofurantoin was tested in man. Materials and methods
Nitrofurantoin and nitrofurantoin tablets 100 mg (EI- Kahira) were used. The antacids were magnesium trisilicate, aluminum hydroxide, magnesium oxide, and calcium carbonate, all of B.P. grade. Bismuth oxycarbonate B.P.C., an ingredient commonly used with antacids, talc B.P., a common excipient in tablet formulations, kaolin and charcoal B.P., model adsor-
0009-9236/79/060857+07$00.70/0 © 1979 The C. V. Mosby Co.
857
858
Naggar and Khalil
Clin. Pharmacol. Ther. June 1979
Table I. Percentage of nitrofurantoin adsorbed per gram adsorbent and percentage eluted* (initial concentration, 3.003 mgllOO ml) Adsorbent
pH of antacid suspension
Magnesium trisilicate Bismuth oxycarbonate Talc Charcoal Kaolin Aluminium hydroxide Magnesium oxide Calcium carbonate
7.6 2.6 2.4 4.0 2.3 6.5 8.1 7.7
Nitrofurantoin adsorbed (%)
99.3 (0.32; 5.58) 53.3 50.5 99.6(0.34; -) 31.7 2.5 26.8 0.00
'Figures in parentheses represent the percentage of the drug eluted using 0.01 N HCl or 0.014 N NaHCOa (second figure).
bents, the latter with a large hydrophobic surface, were also included for comparison. In vitro study. The procedure adopted in adsorption and elution has been reported. 15 The study was done in 0.01 N HCI (pH, 2.2) to simulate gastric pH conditions. Drug concentrations ranged from 0.3 to 6.6 mg/lOO m!. Eluting solutions were 0.01 N HCI and 0.014 N NaHC0 3 (pH, 7.4). In both adsorption and elution studies, nitrofurantoin (protected from light) was assayed spectrophotometric ally at 370 nm. In vivo study. The absorption characteristics of nitrofurantoin and nitrofurantoin-magnesium trisilicate combination were evaluated in 6 adult male volunteers with no known history of urinary tract diseases or hypersensitivity to nitrofurantoin. A crossover design was followed. The subjects were instructed not to take other medication or alcoholic beverage for 14 days prior to the study and through the entire test period. A single lOO-mg nitrofurantoin tablet was taken orally by each volunteer with 150 ml of water (treatment A) or with 150 ml water containing 5 gm magnesium trisilicate (treatment B) after an overnight fast of not less than 8 hr. At least 1 wk elapsed between the two treatments. Subjects were given a light lunch 4 hr after either treatment. No adverse experiences were reported by the subjects. Urine specimens were collected at predetermined time intervals over a 12-hr period; pH and volume were measured. Immediately prior to taking nitrofurantoin, a zero time urine specimen was collected. Drug concentration in the urine was determined by the modified 12 spectrophotomet-
ric method of Conklin and Hollifield3 specific for un metabolized nitrofurantoin. Appropriate urine blank corrections were made. All urine samples were stored in a cool place and protected from light. Results
The percentage nitrofurantoin adsorbed on the different antacids or adsorbents is shown in Table I. For an identical initial concentration of the drug, magnesium trisilicate and charcoal exhibited the greatest adsorption capacity. Bismuth oxycarbonate, talc, kaolin, and magnesium oxide had intermediate adsorption and aluminum hydroxide and calcium carbonate had little or no adsorptive property. Magnesium trisilicate suspension in 0.01 N HCI had a pH of about 7.6. At this pH, nitrofurantoin, a weak acid (pKa, 7.2), will be about half ionized. Depletion of nitrofurantoin from solution, in the presence of magnesium trisilicate, therefore may be due to adsorption on the antacid surface, partially through binding to electron-accepting sites. 13 Adsorption through simple van der Waal's attraction of the nonionized hydrophobic portion of nitrofurantoin is also suggested since charcoal (a model adsorbent with a large hydrophobic surface area and a relatively acidic suspension in 0.01 N HCI, pH 4) as well exhibited a high adsorption power for the drug. Nitrofurantoin-magnesium trisilicate interaction seems rather strong since attempts to elute the drug with solution of physiologic pH values (namely, 0.01 N HCI and 0.014 N NaHC0 3 ) were not successful (Table I). The adsorption isotherm for nitrofurantoin on mag-
Volume 25 Number 6
Magnesium trisilicate-nitroJurantoin interaction
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