Kari T. Kivistö

Interference of dairy products with the absorption of ciprofloxacin

The effects of milk and yogurt on the bioavailability of ciprofloxacin were studied in seven healthy volunteers in a randomized crossover trial. After an overnight fast, 500 mg ciprofloxacin was given with 300 ml water, milk, or yogurt. Plasma ciprofloxacin concentrations were significantly (p < 0.05) lower during the milk and yogurt phases from ½ to 10 hours; at ½ hour the concentration was reduced by 70% by milk and by 92% by yogurt. Milk reduced the peak plasma concentration by 36% (p < 0.05) and yogurt by 47% (p < 0.05). The extent of bioavailability, measured as the total area under the plasma concentration‐time curve and 24‐hour urinary excretion of ciprofloxacin, was reduced by 30% to 36% by milk and yogurt (p < 0.05). We conclude that the absorption of ciprofloxacin can be reduced by concomitant ingestion of milk or yogurt. To avoid therapeutic failures in infections where the causative organism is only moderately susceptible, ingestion of large amounts of dairy products in liquid form with ciprofloxacin is not recommended.

Enhancement of Drug Absorption by Antacids

SummaryAntacids are widely used for many disorders. The potential of antacids to interact with other concomitantly ingested drugs is well recognised. These interactions usually result in reduced or delayed absorption of the affected drug. However, this is not always the case.In contrast to aluminium hydroxide, magnesium hydroxide and sodium bicarbonate can enhance the absorption of some drugs. For example, magnesium hydroxide can increase the rate and sometimes even the extent of absorption of certain nonsteroidal anti-inflammatory drugs (e.g. tolfenamic acid, mefenamic acid and ibuprofen), sulphonylurea antidiabetic agents [e.g. glipizide, glibenclamide (glyburide) and tolbutamide] and the oral anticoagulant dicoumarol (bishydroxycoumarin). These weakly acidic drugs are nonionised at gastric pH, but are sparingly water soluble. Elevation of the gastric pH by administration of magnesium hydroxide or sodium bicarbonate increases the solubility and absorption of such sparingly water soluble agents. Chelate formation may be involved in the increased absorption of dicoumarol by magnesium hydroxide. In combination antacids containing both aluminium hydroxide and magnesium hydroxide, the absorption enhancing effect of magnesium hydroxide seems to be counterbalanced by the opposing effects of aluminium hydroxide.The clinical significance of increased drug absorption is not clear. However, accelerated and enhanced absorption of analgesic drugs may be beneficial when rapid pain relief is desired. In contrast, an unexpectedly increased hypoglycaemic or anticoagulant effect may be potentially dangerous. Therefore, a knowledge of the potential effect of antacids on the absorption of other drugs is clinically important.

A Review of Assay Methods for Cyclosporin

SummaryCyclosporin is a unique immunosuppressive agent with a narrow therapeutic range. The pharmacokinetics of the drug present substantial within- and between-patient variability and drug interactions can significantly alter blood cyclosporin concentrations. Monitoring of cyclosporin concentrations in blood is an invaluable and essential aid in adjusting dosage to ensure adequate immunosuppression while minimising toxicity. The principal rationale behind therapeutic monitoring of cyclosporin is the fact that the incidence of rejection is higher at low cyclosporin concentrations and toxicity occurs more often at high concentrations. In renal transplant recipients, cyclosporin concentrations help to discriminate between insufficient immunosuppression and cyclosporin-induced nephrotoxicity.There are several methods available, both specific and nonspecific, for the routine measurement of cyclosporin. Radioimmunoassay and fluorescence polarisation immunoassay are most widely employed, while high performance liquid chromatography remains the reference procedure. The allegedly specific immunoassays tend to slightly overestimate the actual blood cyclosporin concentrations. There is a need for assay systems capable of measuring the biological activity of cyclosporin. Cyclosporin concentrations should be determined by a specific method, using whole blood as the sample matrix. The routine monitoring of individual cyclosporin metabolites is not warranted, but characterising the metabolite pattern of cyclosporin by concomitant use of a nonspecific and a specific assay can be clinically useful in patients with cyclosporin-associated toxicity or impaired liver function.In organ transplantation, measurement of blood cyclosporin concentration should be continued periodically as long as the therapy continues, whereas monitoring is only indicated in special circumstances in patients with autoimmune and other nontransplant diseases. The assessment of a ‘therapeutic window’ for cyclosporin is complicated for several reasons and definite target ranges cannot be given. Cyclosporin concentrations should always be interpreted in conjunction with the recent blood concentration history and other relevant clinical and laboratory data.

Enhancement of absorption and effect of glipizide by magnesium hydroxide

The effects of magnesium hydroxide on the pharmacokinetics and pharmacodynamics of glipizide were studied in eight healthy volunteers in a randomized crossover trial. After an overnight fast, 5 mg glipizide was given with either 150 ml water or water containing 850 mg magnesium hydroxide. Magnesium hydroxide increased the areas under the plasma glipizide concentration‐time curves (AUC) from 0 to ½ hour and from 0 to 1 hour by 180% (p < 0.05) and 69% (p < 0.05), respectively. The peak plasma concentration, time to peak, total AUC, elimination half‐life, and mean residence time of glipizide remained unchanged. The incremental plasma insulin area from 0 to ½ hour increased by 85% (p < 0.05), and the time to maximal insulin response was reduced (p < 0.05) during the magnesium hydroxide phase. The corresponding decremental plasma glucose area increased fourfold (p < 0.05), and the maximal glucose decrease was 35% greater (p < 0.05) than during the control phase. We conclude that the concomitant ingestion of magnesium hydroxide and glipizide may result in accelerated absorption of glipizide and increased early insulin and glucose responses.

Prevention of Chloroquine Absorption by Activated Charcoal

1 The ability of activated charcoal to prevent the absorption of chloroquine was investigated in healthy volunteers, and the effect of the charcoal-chloroquine ratio on the completeness of binding was studied in vitro. 2 After an overnight fast, six subjects ingested 500 mg of chloroquine phosphate with water, and another group of six subjects ingested 25 g of charcoal suspension within 5 min of chloroquine intake. The concentrations of chloroquine in plasma and whole blood were measured by high-performance liquid chromatography for 192 h. 3 Activated charcoal reduced the areas under the plasma and whole blood chloroquine concentration-time curves (AUC) from 0 to 192 h, the total AUCs, and the peak concentrations by 99% (P < 0.001). 4 Chloroquine was very effectively bound by activated charcoal in vitro, even at low charcoal-chloroquine ratios. For example, at a ratio of 5:1, about 98% of chloroquine was bound. 5 Activated charcoal should be very effective in reducing the absorption of that fraction of chloroquine dose which is in the stomach at the time of charcoal administration. Because the acute toxicity of chloroquine is extremely high and death usually occurs within 1-3 h of overdosage, charcoal should be given as early as possible in suspected chloroquine intoxication.

Different effects of products containing metal ions on the absorption of lomefloxacin

The effects of different cation containing products on the absorption of lomefloxacin were evaluated in eight healthy volunteers in a five‐way randomized crossover study. The treatments were lomefloxacin alone, lomefloxacin with milk (300 ml), lomefloxacin with calcium carbonate (corresponding to 500 mg calcium), lomefloxacin with ferrous sulfate (corresponding to 100 mg elemental iron), and lomefloxacin with sucralfate (1 gm). Treatments were separated by a 7‐day washout period. The bioavailability of lomefloxacin was significantly reduced when it was given with sucralfate; the area under the plasma drug concentration–time curve (AUC) from 0 to 24 hours was reduced by 51% (p < 0.05). Ferrous sulfate reduced the maximum plasma concentration of lomefloxacin by 26% (p < 0.05), the total amount of lomefloxacin recovered in urine by 15% (p < 0.05), and the AUC by 13% (p = 0.26). Calcium carbonate and milk had no significant effects on the bioavailability of lomefloxacin. We conclude that concomitant use of lomefloxacin and sucralfate should be avoided. It may also be advisable not to take lomefloxacin with ferrous sulfate, although this interaction is probably of no clinical significance. Calcium carbonate and milk do not affect lomefloxacin absorption.

Effect of Activated Charcoal on the Absorption of Amiodarone

1 The ability of activated charcoal to prevent the absorption of amiodarone was studied in 18 healthy volunteers, divided into three groups of six subjects. 2 All subjects were administered a single dose of 400 mg amiodarone; one group ingested the drug with water only (control) and the second with 25 g of activated charcoal as a water suspension. The subjects in the third group were given 25 g of charcoal immediately after the 1.5 h blood sample. 3 The extent of amiodarone absorption was reduced by about 98% by simultaneously administered charcoal (P < 0.001); taking charcoal 1.5 h after amiodarone still resulted in a 50% reduction in amiodarone bioavailability (P < 0.05). 4 These results indicate that activated charcoal should be effective in preventing amiodarone absorption in acute poisoning.

The Effect of Activated Charcoal on the Absorption and Elimination of Astemizole

1 The effect of activated charcoal on the absorption and elimination of astemizole and its metabolites was studied in healthy volunteers. 2 Subjects were divided into three groups containing seven subjects each. One group received 30 mg of astemizole with water only (control) and another group with 25 g of activated charcoal. The third group received multiple doses (12 g) of charcoal from 6 h onwards twice daily for 8 days. The concentrations of astemizole and its metabolites in plasma were measured by radioimmunoassay for 192 h. 3 Activated charcoal, administered immediately after astemizole ingestion, reduced the absorption of astemizole by 85% (P<0.001). Multiple doses of activated charcoal, administered throughout the period of astemizole elimination, had no significant effect on the rate of elimination or the area under the curve from 0 to 192 h. 4 The absorption of astemizole from the gastrointestinal tract can be effectively prevented with activated charcoal. Because astemizole is rapidly absorbed, charcoal should be administered as soon as possible in acute astemizole poisoning. Multiple doses of charcoal do not seem to shorten the elimination half-life of astemizole.

Failure of Oral Activated Charcoal to Accelerate the Elimination of Amiodarone and Chloroquine

1 The effect of activated charcoal on the elimination of amiodarone and chloroquine was studied in the rat. 2 The study consisted of two separate experiments. Amiodarone and chloroquine were injected subcutaneously at doses of 200 mg kg-1 and 100 mg kg-1, respectively. Six rats in both experiments were put on a charcoal-containing diet 48 h after drug administration, while the control groups remained on a normal diet. 3 Treatment with repeated oral activated charcoal had no effect on the true elimination of amiodarone and chloroquine. 4 These results suggest that, after the distribution of amiodarone and chloroquine into peripheral compartments, their rate of elimination cannot be significantly accelerated with multiple oral doses of activated charcoal.