Sorbitol induced diarrheal illness model.

Twenty-five normal volunteers participated in this study to develop a model of diarrheal illness. The ideal model would induce diarrhea with consistent onset of 18 to 24 hours duration of watery stools, and have few associated symptoms. Groups of five to six each were studied. Volunteers who received castor oil experienced watery stools of short duration associated with abdominal cramps, making it an unacceptable model of disease. Sauerkraut and prune juices inconsistently caused watery stool. Seventy percent sorbitol induced watery diarrhea with few associated symptoms, and of five to six hours duration. The administration of 45 ml of 70% sorbitol six hours apart induced watery stools that met our objective and should be a suitable model for future drug testing of anti-diarrheal medications.

Influence of study design in assessing food effects on absorption of erythromycin base and erythromycin stearate.

We performed a series of six single-dose and multiple-dose studies to evaluate the effect of food on the absorption of erythromycin base and erythromycin stearate. When we used a single-dose design, we found that an unprotected erythromycin base preparation was absorbed extensively if a prolonged fast preceded administration of the drug. A shorter faster period (as occurs in clinical settings) dramatically reduced the absorption of unprotected base; however, film-coated tablets seemed to be as well protected as and were absorbed more rapidly than enteric-coated tablets when they were evaluated by single-dose testing procedures. In contrast, when a commercially available film-coated preparation of erythromycin base was evaluated in multidose fashion between meals (fasting), the drug was about 25% less well absorbed than commercially available enteric-coated base tablets. Finally, when commercially available film-coated erythromycin base and stearate formulations were administered with meals, both film-coated preparations were 43 to 59% less well absorbed than the enteric-coated base formulation. Furthermore, the enteric-coated base formulation performed equally well when administered either every 6 h between meals (fasting) or four times a day (immediately after meals and at bedtime). These studies document the need for multidose bioavailability techniques when the bioavailabilities of acid-labile drugs are evaluated.

Comparative bioavailability evaluation of erythromycin base and its salts and esters. I. Erythromycin estolate capsules versus enteric-coated erythromycin base tablets.

A randomized crossover study in 16 healthy volunteers given multiple doses of erythromycin base enteric-coated tablets or erythromycin estolate capsules revealed essentially no difference in the resultant plasma concentration of bioactive erythromycin. This similarity in bioactivity persisted despite the fact that total eryghromycin levels (bioactive erythromycin base plus bioinactive erythromycin propionate) were at least three times higher after administration of the estolate than after administration of the base.

Clinical bioavaiability of nitrofurantoin--a case of bioinequivalence.

In a crossover study of the bioavailability of marketed nitrofurantoin tablets, there were significant differences in the urinary excretion of nitrofurantoin suggestive of bioavailability problems with this drug. Standard in vitro assessments of dissolution rate and disintegration time were not correlated with bioavailability and failed to detect 3 to 18 fold differences in the amount of nitrofurantoin absorbed. In fact, four lots, made by the same manufacturer had almost identical in vitro measurements (dissolution rate; distinegration time), yet two of these lots were only 6.6 and 26% as available as the reference nitrofurantoin product, and two others were comparatively available. The need for the development of an in vitro - in vivo correlation for control of lot to lot uniformity has clearly been demonstrated for nitrofurantoin. Such correlations must include tests other than those presently required.

Antibiotic batch certification and bioequivalence.

All antibiotics marketed in the United States must undergo batch certification by the Food and Drug Administration. It is often assumed that the different brands of a particular antibiotic that pass in vitro batch certification tests have equal in vivo bioavailability. The fallacy of this assumption is clearly supported for commercially available lots of tetracycline hydrochloride that had passed batch certification tests yet had different serial serum concentrations.