Interactions Affecting Drug Absorption

Interaction studies in dogs have indicated that antacids significantly decrease the oral bioavailablity of cefixime. Twelve healthy adult male volunteers participated in a randomized, four-way crossover trial to evaluate the influence of an aluminum-magnesium antacid (Maalox; 20 ml) on the pharmacokinetics of cefixime (400 mg). Regimens were (i) cefixime alone; (ii) cefixime simultaneous with antacid; (iii) cefixime 2 h before antacid; and (iv) cefixime 2 h after antacid. Serial blood and urine samples were collected over a 24-h period following each dose of cefixime. There was a 1-week washout interval between regimens. Cefixime concentrations in serum and urine were analyzed by high-performance liquid chromatography. Maximum cefixime concentrations in serum for regimens i through iv were (mean ± standard deviation) 4.9 ± 1.4, 5.7 ± 1.3, 5.1 ± 1.0, and 5.5 ± 1.5 ,ug/ml, respectively. Corresponding values for area under the serum concentration-time curve extrapolated to infinity were 38.3 ± 14.5, 42.8 ± 13.9, 38.5 ± 9.8, and 41.6 ± 16.7 ,ug-h/ml. There was a trend toward increased concentrations in serum and area under the curve of cefixime when it was administered concomitantly with antacid; however, these differences were not statistically significant (P > 0.05; analysis of variance). We conclude that single-dose administration of an aluminum-magnesium antacid does not significantly decrease the oral bioavailability of cefixime.Nonsystemic antacids containing aluminum and magnesium are widely used in the treatment of gastrointestinal disorders. Coadministration of antacids has been found to interfere with the absorption of many drugs, including tetracyclines, cefuroxime axetil, and fluoroquinolone antibiotics (1,6,10,12).Cefixime is an investigational oral cephalosporin that has good in vitro activity against a broad range of respiratory and urinary tract pathogens and is very stable against various P-lactamases (9). It has an absolute bioavailability of 40 to 52%, and food does not interfere with the overall extent of drug absorption (3)(4)(5) Washington, Pa.). Regimens were (i) cefixime alone, (ii) cefixime simultaneous with antacid, (iii) cefixime 2 h before antacid, and (iv) cefixime 2 h after antacid. All doses of cefixime were administered as one 400-mg tablet followed by 240 ml of water, and each dose of antacid was administered as a 20-ml of suspension. Nov. 1989Nov. , p. 1994Nov. -1997 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, and 24 h postdose. After coagulation and centrifugation, the separated serum was stored frozen at -70°C until assayed. Urine was collected during the intervals from -2 to 0 (baseline), 0 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, and 12 to 24 h postdose. The total volume of urine within each interval was recorded, the pH was measured, and a 10-ml portion of each sample was frozen at -70°C until analyzed. Serum and urine samples were assayed within 6 weeks. Cefixime assay. Cefixime concentrations in serum and urine were measured by reversed-phase high-performance liquid chromatogra...

Section: Discussionsupporting

confidence: 84%

Influence of an antacid containing aluminum and magnesium on the pharmacokinetics of cefixime

Healy

Sahai

Sterling

et al. 1989

“…Interactions involving coadministration of drugs with various antacid preparations are well documented (23,51). Several mechanisms of action exist: raising the pH in the gastrointestinal tract, increasing solubility of acids and decreasing solubility of bases, adsorption to insoluble antacid particles, chelation to insoluble complexes, influencing the stomach-emptying rate and gastric acidity (15,18,46).…”

Section: Discussionmentioning

confidence: 99%

Influence of ranitidine, pirenzepine, and aluminum magnesium hydroxide on the bioavailability of various antibiotics, including amoxicillin, cephalexin, doxycycline, and amoxicillin-clavulanic acid

Deppermann

Lode

Höffken

et al. 1989

Two randomized double-blind crossover studies and one randomized crossover study were performed to document possible drug-drug interactions between antacids (aluminum magnesium hydroxide, 10 ml per dose for 10 doses), antimuscarinic drugs (pirenzepine, 50 mg per dose for 4 doses), and H2-blockers (ranitidine, 150 mg per dose for 3 doses) and amoxicillin (1,000 mg), cephalexin (1,000 mg), doxycycline (200 mg), and amoxicillin-clavulanic acid (625 mg). Ten healthy volunteers participated in each study. Concentrations in serum and urine were measured by bioassay, and pharmacokinetic parameters were calculated by the usual open one-or two-compartment models (statistics were determined by the Wilcoxon test). The antacid, pirenzepine, and ranitidine had no influence on the bioavailability of amoxicillin, cephalexin, and amoxicillinclavulanic acid. Only small differences could be observed in the pharmacokinetic parameters, but they are not of therapeutic importance. However, the antacid caused a significant (P < 0.01) reduction in the gastrointestinal absorption of doxycycline (area under the concentration-time curve, 38.6 + 22.7 mg * h/liter, fasting; 6.0 + 3.2 mg. h/liter, with antacid), resulting in subtherapeutic levels of doxycycline.

“…Coadministration of milk or yoghurt reduced the extent of norfloxacin absorption and the mean peak concentration in plasma by approximately 50%. Taking of norfloxacin with these liquid dairy products should be avoided.Food-drug interactions have been studied extensively in recent years, but because of the complex nature of these interactions, general guidelines for clinical practice cannot be given (8,15). Food can influence drug absorption by a wide variety of mechanisms, resulting in changes in both the rate and the extent of bioavailability.…”

mentioning

confidence: 99%

“…Food-drug interactions have been studied extensively in recent years, but because of the complex nature of these interactions, general guidelines for clinical practice cannot be given (8,15). Food can influence drug absorption by a wide variety of mechanisms, resulting in changes in both the rate and the extent of bioavailability.…”

mentioning

confidence: 99%

Inhibition of norfloxacin absorption by dairy products

Kivistö

Ojala-Karlsson

Neuvonen

1992

Seven healthy subjects received, after an overnight fast, a single 200-mg oral dose of norfloxacin with water, whole milk, and unflavored yoghurt. Coadministration of milk or yoghurt reduced the extent of norfloxacin absorption and the mean peak concentration in plasma by approximately 50%. Taking of norfloxacin with these liquid dairy products should be avoided.Food-drug interactions have been studied extensively in recent years, but because of the complex nature of these interactions, general guidelines for clinical practice cannot be given (8,15). Food can influence drug absorption by a wide variety of mechanisms, resulting in changes in both the rate and the extent of bioavailability. The formation of poorly absorbed chelate complexes is one important mechanism of absorption interactions. A classic example is the interference of milk (calcium), iron salts, and antacids containing polyvalent cations with tetracycline absorption (7). Similarly, the absorption of fluoroquinolones is considerably impaired in the presence of cations such as calcium, iron, magnesium, zinc, and aluminum (5, 10-12).Concurrent ingestion of food with fluoroquinolones has been shown not to interfere with their absorption to a clinically significant degree (4,6,14). For example, Frost and coworkers (1) found that the bioavailability of ciprofloxacin is unaffected by a breakfast containing a high amount of calcium. However, we recently demonstrated (9) that the bioavailability of ciprofloxacin is significantly reduced when it is taken together with 300 ml of milk or yoghurt. To our knowledge, the effects of dairy products on the absorption of other fluoroquinolones have not been studied. The objective of this study was to characterize the effects of two liquid dairy products, whole milk and unflavored yoghurt, on the absorption of norfloxacin.A randomized, three-period, crossover design was used. Each treatment period was separated by a 7-day washout period. Four male and three female volunteers, aged 19 to 24 years and weighing 55 to 90 kg and considered healthy on the basis of medical history, physical examination, and routine laboratory tests, participated in the study. The volunteers were thoroughly informed in writing, and verbal consent was obtained. The study protocol was approved by the ethics committee of the Turku University Medical School.After an overnight fast, the subjects ingested 200 mg of norfloxacin (one 200-mg Lexinor tablet; Astra Pharmaceuticals, Sodertalje, Sweden) with 300 ml of water, 300 ml of whole milk (Valio, Helsinki, Finland), or 300 ml of unflavored yoghurt (Valio). The temperature of water, milk, and yoghurt was 12 to 14°C at the time of administration. The milk and yoghurt portions contained 360 and 450 mg of calcium, 9.6 and 11.4 g of protein, 11.7 and 7.5 g of fat, and 14.1 and 15 g of carbohydrates, respectively. The subjects were allowed to undertake their normal daily activities immediately after receiving the norfloxacin dose; fasting was continued for 3 h. Blood samples for the norfloxacin assay * ...