Chronic effects of an alpha-glucosidase inhibitor (Bay o 1248) on intestinal disaccharidase activity in normal and diabetic mice

Bay o 1248 is a potent alpha-glycosidase inhibitor that reduces postprandial hyperglycemia when administered p.o. with sucrose or maltose. The compound binds to and competitively inhibits the alpha-disaccharidases and is also readily absorbed across the intestinal mucosa. To evaluate its effect on the activity of disaccharidases and on metabolic control, groups of obese diabetic mice (C57BLKsJ db/db) were given the drug for periods of 3, 7 and 84 days as a drug food mixture (5 or 10 mg/100 g of food). Nondiabetic mice of the same strain were dosed for 3 and 7 days. The drug did not influence body growth, food intake or fasting blood glucose. However, urine glucose excretion was significantly decreased at the higher dose in the diabetic mice. The drug had no effect on the protein content of jejunum (proximal and middle thirds) or ileum (distal third) of the small intestine. The activity of sucrase and maltase was significantly decreased in practically all segments of the small intestine in both diabetic and nondiabetic mice. These changes were evident after 3 days of drug administration. Lactase was not affected by the drug. The mechanism underlying these changes, although unclear, is of significant interest and deserves further investigation.     

Pharmacokinetics of 3''-fluoro-3''-deoxythymidine and 3''-deoxy-2'',3''-didehydrothymidine in rhesus monkeys.

3'-Fluoro-3'-deoxythymidine and 3'-deoxy-2',3'-didehydrothymidine are nucleoside analogs which inhibit human and simian immunodeficiency virus in vitro. The pharmacokinetic properties of these compounds in rhesus monkeys after intravenous, oral, and subcutaneous administration of the drug were compared. Half-lives, total clearances, and steady-state volumes of distribution of the two drugs were determined. The half-lives for the drugs by the different routes were between 0.58 and 1.4 h. Oral bioavailability of 3'-deoxy-2',3'-didehydrothymidine was incomplete, with an average of 42% +/- 15% of the dose reaching the systemic circulation. Absorption of 3'-fluoro-3'-deoxythymidine after oral administration was variable, with bioavailability ranging from 21 to 95%. Bioavailability after subcutaneous administration ranged from 59 to 77% for 3'-deoxy-2',3'-didehydrothymidine and from 52 to 59% for 3'-fluoro-3'-deoxythymidine. The ratio of concentrations in cerebrospinal fluid and serum for the drugs was about 0.15 at 1 h after drug administration and was independent of the route of administration, suggesting that a nucleoside carrier-mediated process is involved in the transport of these compounds to the central nervous system. Because of the similar metabolism of nucleoside analogs in monkeys and humans, the potential glucuronide formation was assessed. Whereas the glucuronide of 3'-fluoro-3'-deoxythymidine was readily detected in urine, the amount of 3'-deoxy-2',3'-didehydrothymidine glucuronidated was small or not detectable in one-half of the urine samples. Pharmacokinetic parameters for the two drugs were similar to each other and analogous to those for 3'-azido-3'-deoxythymidine in monkeys, suggesting that the same dose and scheduling of the drug can be used for all three compounds in prophylactic and therapeutic efficacy drug studies in rhesus monkeys.     

Effect of food on the bioavailability of cyclandelate from commercial capsules

The bioavailability of five capsules of cyclandelate that are commercially available in Japan was determined in ten healthy volunteers by measuring mandelic acid (a main metabolite of cyclandelate) excreted in the urine. Bioinequivalence among the five capsules was demonstrated. The relative cumulative excretion of mandelic acid of the most poorly bioavailable capsule was 38% of the most highly bioavailable capsule. The effect of food on the bioavailability of these two capsules was investigated by use of two different kinds of food, one containing fat and one containing high carbohydrates but very low fat. The bioavailability of the two capsules was increased when subjects consumed both types of food before drug administration, although there was a greater effect on bioavailability with food containing fat. This suggests that the absorption of cyclandelate was incomplete in fasting subjects, even from the capsule with the highest bioavailability. Bioinequivalence between the two capsules remained after postprandial drug administration.     

Nanoparticles with specific bioadhesive properties to circumvent the pre-systemic degradation of fluorinated pyrimidines.

The aim was to evaluate the potential of specific bioadhesive nanoparticles to increase the oral bioavailability of pre-systemic degraded drugs, using 5-fluorouridine (FURD) as model. For this purpose, poly(methylvinylether-co-maleic anhydride) nanoparticles (NP), NP coated with albumin (BSA-NP) and NP treated with albumin and 1,3-diaminopropane (BD-NP) were used. All the formulations displayed a similar size and drug loading. However, BSA-NP showed a tropism for the stomach, NP developed adhesive interactions with both the stomach and middle portions of the small intestine and BD-NP with the distal regions of the small intestine. These formulations were orally administered to laboratory animals and the FURD levels in plasma, tissues and urine were quantified at different times. From the urine data, the FURD bioavailability when loaded in either BSA-NP or NP was about 79% and 21%, respectively. For the control oral solution and BD-NP this parameter was 11% and 2%, respectively. FURD metabolism in gut was assessed by HPLC analysis of the lumen content. A FURD metabolite was found. Comparing the three nanoparticle formulations, the presence of the metabolite in the lumen contents was significantly higher for BD-NP than for NP and BSA-NP. In summary, the use of bioadhesive nanoparticles with tropism for the stomach mucosa may be considered as an adequate alternative to increase the bioavailability of some pre-systemic metabolised drugs.     

Low bioavailability of amoxicillin in rats as a consequence of presystemic degradation in the intestine.

Several studies have been carried out to elucidate the causes of the low oral bioavailability of amoxicillin in rats. The hepatic first-pass effect of the antibiotic was estimated by comparing the area under the plasma drug concentration-versus-time curve from time zero to infinity (AUC0-infinity) obtained after injecting the drug into a mesenteric vein with the AUC0-infinity value obtained after injecting the drug into the jugular vein of conscious rats. No hepatic first-pass effect was detected. The bioavailability of amoxicillin after intraduodenal administration was only 51%, and the fraction of the dose remaining in the intestine at the end of the experiment was 4.5%. This was far less than the fraction that did not reach systemic circulation, which indicates a presystemic loss of drug, probably at the intestine. In vitro studies corroborated the fact that amoxicillin is subjected to presystemic degradation by intestinal juices and intestinal tissues. The greatest loss of drug occurred in the complete intestine (45% of the initial amount), and it was mainly due to the action of intestinal tissues (28% of the initial amount) but was also due to the action of intestinal juices (15% of the initial amount). The absorption of amoxicillin in three parts of the intestine (upper, middle, and lower) was also evaluated. The largest AUC0-infinity value and the highest plasma drug levels were obtained when amoxicillin absorption took place in the middle intestine. The smallest AUC0-infinity value and the lowest plasma drug levels corresponded to absorption from the upper intestine.     

Anthocyanidins but not anthocyanins inhibit P‐glycoprotein‐mediated calcein extrusion – possible implication for orally administered drugs

P‐glycoprotein (P‐gp) inhibition represents a promising therapeutic strategy for oncologic patients. The inhibition by naturally occurring anthocyans would bring certain benefits. Unfortunately, due to the low bioavailability and consequently low blood level, they cannot be used for cancer therapy. However, due to the food supplementation, significant concentration can raise up in the intestine, where P‐gp is abundantly expressed. As many drugs are orally taken, simultaneous administration might affect the concentration of these drugs in the blood. Here, we found that anthocyanidins (aglycons) but not anthocyanins (glycosides) can significantly inhibit P‐gp up to 60% of positive control, verapamil. This inhibitory activity was observed for 500 μm concentrations of malvidin and pelargonidin. We conclude that these compounds may be the source of food–drug interactions either for orally taken drugs or for intravenously administered drugs eliminated via biliary excretion which are the substrates of P‐gp.     

Absorption of water-soluble compounds with different molecular weights and.

The absorption of water soluble compounds with different molecular weights, such as phenol red (MW 354), trypan blue (MW 960), fluorescein isothiocyanate dextrans, (MW 4400 and 9100) was studied in the lung, nasal cavity, buccal cavity, small and large intestine of rats. For all the compounds, maximal absorption was observed when administered to the lung. The rank order of absorption of each compound from various administration sites was lung>small intestine> or =nasal cavity> or =large intestine> or =buccal cavity. In addition, the relationship between logarithm absorption % of the compounds from various administration sites and logarithm molecular weights of these compounds was examined. The absorption of compounds gradually decreased with increasing molecular weight for each site of administration. Moreover, the absorption of [Asu1.7]-eel calcitonin (ECT) from these sites and the effect of 10 mM sodium glycocholate, an absorption enhancer, on its absorption were also investigated in rats. When ECT alone was administered into these sites, the lung had the best absorption site of ECT, followed by the nasal cavity, the large intestine, the small intestine and the buccal cavity. Therefore, the absorption of ECT was also dependent on the administration site, although the rank order of absorption % of ECT was different from the other compounds. Sodium glycocholate (NaGC) remarkably increased ECT absorption from the small intestine, while we found marginal increase in its absorption from the lung even in the presence of NaGC. These findings provided useful fundamental information that might aid in the selection of administration routes for drugs of differing molecular weights including peptide drugs as far as the degree of drug absorption is concerned.     

A comparative experimental study of the effects of diclofenac and ketoprofen on the small-bowel mucosa of canines

The aim of this experimental study was to investigate the effect of diclofenac sodium and ketoprofen, two non-steroidal anti-inflammatory drugs (NSAIDs) with different excretion pathways, and the role of other enteric factors during simultaneous administration of these drugs on the development of mucosal lesions of the small intestine in canines. Twenty-five animals were divided into three groups. Group I included 10 canines, 5 with diclofenac sodium (group Ia) and 5 with ketoprofen administration (group Ib). Group II included 5 animals in which a segment of ileum was surgically isolated from the rest of the small intestine. Group III included 10 animals in two subgroups of 5; a segment of ileum was surgically isolated in both subgroups; groups IIIa received diclofenac and group IIIb ketoprofen. Histological examination of the specimens taken revealed macroscopic and microscopic mucosal lesions in 5/5 animals in group Ia, whereas none of the 5 animals in group Ib had any lesions. Group II did not reveal any mucosal lesions. Three out of 5 animals (60%) administered diclofenac in group IIIa had intestinal mucosal lesions, but none of the 5 revealed lesions in the isolated loop of ileum. No lesions were observed in the isolated loop or in the rest of the intestinal mucosa in the animals in group IIIb. Our results suggest that NSAIDs produce intestinal mucosal lesions not only when administered per mouth but also after intramuscular administration. Diclofenac, unlike ketoprofen, was responsible for the development of lesions in the intestinal mucosa. The role of drugs and/or their metabolites in the intestine and certain other factors must still be determined.     

Pharmacokinetics, tissue distribution and bioavailability of clozapine solid lipid nanoparticles after intravenous and intraduodenal administration.

Clozapine, a lipophilic effective atypical antipsychotic drug, has very poor oral bioavailability (<27%) due to first pass effect. Clozapine solid lipid nanoparticles have been developed using various triglycerides (trimyristin, tripalmitin and tristearin), soylecithin 95%, poloxamer 188 and stearylamine as a positive charge inducer by hot homogenization followed by ultrasonication method. Particle size and charge measurements were made with Malvern Zetasizer. Pharmacokinetics of clozapine incorporated in solid lipid nanoparticles (SLNs), after intravenous (i.v.) administration to conscious male Wistar rats were studied. The aim of this research was to find out whether the bioavailability of clozapine can be improved by administering clozapine SLN duodenally to rats. Tissue distribution studies of clozapine SLN and suspension were carried out in Swiss albino mice. Average size and zeta potential of SLNs of different lipids with stearylamine ranged from 96.7+/-3.8 to 163.3+/-0.7 nm and 21.3+/-1.3 to 33.2+/-0.6 mV, respectively. AUC((0-infinity)) was increased (up to 2.91-fold) and clearance was decreased (up to 2.93-fold) when clozapine entrapped in SLNs with stearylamine were administered intravenously. Bioavailability of clozapine SLNs were 2.45- to 4.51-fold after intraduodenal administration compared with that of clozapine suspension. In tested organs, the AUC and MRT of clozapine SLNs were higher than those of clozapine suspension especially in brain and reticuloendothelial cell-containing organs. These results indicate that SLN are suitable drug delivery system for the improvement of bioavailability of lipophilic drugs such as clozapine.     

Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats: the contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells

The bioavailability of orally administrated cyclosporine A (CsA) is poor and variable in liver transplantation recipients. Little information is available about the effect of liver ischemia-reperfusion (I/R) injury, which is associated with liver transplantation, on the intestinal first-pass metabolism of CsA. In the present study, we investigated the pharmacokinetics of CsA after liver I/R and assessed the effect of liver I/R via CYP3A and P-glycoprotein (P-gp) on its intestinal first-pass metabolism. When CsA alone was administrated orally, the area under the concentration-time curve (AUC) in the I/R rats was significantly decreased compared with that in the sham rats. On the other hand, there were no significant differences in the AUC between I/R and sham rats when CsA was administrated intravenously or orally with ketoconazole. After intraloop administration of CsA to the small intestine (upper, middle, and lower portions) of the I/R and sham rats, the AUC(0-15 min) in the upper intestine was significantly lower in the I/R rats than in the sham rats. CYP3A activity and the expression levels of P-gp in the upper intestine of the I/R rats were significantly higher than those of the sham rats. Our study clearly demonstrates for the first time that liver I/R decreases the oral bioavailability of CsA and that this is attributable principally to increased first-pass metabolism mediated by CYP3A and P-gp in the upper small intestine. The present findings provide useful information for the etiology of liver I/R injury and appropriate use of CsA after liver transplantation.     

The influence of food on nitrofurantoin bioavailability.

The effect of food on the absorption of five commercial dosage forms of nitrofurantoin varying widely in drug release and dissolution characteristics was assessed in man after oral administration. Four healthy fasting and nonfasting male subjects received, in a crossover fashion, a single 100-mg dose of microcrystalline nitrofurantoin as an aqueous suspension, three different compressed tablets, and a single 100-mg dose of macrocrystalline nitrofurantoin in a capsule. Both the absorption and the duration of therapeutic urinary concentrations of nitrofurantoin were significantly increased after administration of the five products to nonfasting subjects. The enhancement in the bioavailability of the drug in the presence of food ranged from 20% to 400%, with the greatest absorption-enhancing effect occurring with those dosage forms exhibiting the poorest dissolution characteristics. It is concluded that single-dose comparative bioavailability studies of drug products normally administered with food should be performed in both nonfasting and fasting subjects.     

Interactions of phytotherapeutic drugs,foods and drinks with medicines

Phytotherapeutic preparations contain a large number of pharmacologically active components. Protective systems have evolved to detoxify and eliminate these xenobiotics. Among them is the cytochrome P450 system and the transporter p-glycoprotein in intestine and liver that control the absorption, biotransformation and elimination of drugs. Components of phytotherapeutic preparations can interfere with the function of these systems and lead to interactions with drugs. St John's wort, for example, induces the expression of p-glycoprotein and CYP3A4 in liver and intestine and thereby decreases the activity of other drugs. Garlic extracts as well may decrease the activity of drugs that are substrates for CYP3A4. In contrast, grapefruit juice inhibits intestinal CYP3A4. This results in a higher bioavailability of some drugs and possibly more adverse effects. Some relevant interactions were only detected after many years of widespread use, indicating that the treating physician should not only inquire about a change in co-medication but also about the use of alternative medicines or a change in dietary habits when a patient presents with unexpected and unusual adverse effects or a sudden loss of drug efficacy. It would be desirable if more information regarding the potential for interactions with commonly used drugs was available prior to registration of new phytotherapeutic preparations in order to document their safety for patients who require continuous treatment with a drug because of a chronic disease.     

Intravenous self-administration of drugs in rats

A standardized self-administration procedure in rats was used to determine the intravenous self-administration liability of graded doses of various drugs. Self-administration was reliably established with the tested addictive drugs (morphine, heroin, fentanyl and d-amphetamine), but not with the nonaddictive drugs (chlorpromazine and nalorphine). However, 1 out of 14 animals on nalorphine clearly demonstrated self-administering behavior. Self-administration was observed with delta1-tetrahydrocannabinol, but the percentage of animals (40% on the highest dose) that initiated this behavior and the amount of drug intake were low in comparison with amphetamine and narcotics. Concerning the narcotic drugs, approximate ED50 values for self-administration under the described conditions were calculated (morphine: 0.65; heroin: 0.05; fentanyl: 0.0025 mg/kg/injection). Total daily drug intake was related to the unit dose delivered per injection in that a higher drug dosage led to more drug intake. In experiments with heroin, this relationship was not caused by prior forced injections. The approximate ED50 value for amphetamine appeared to be 0.145 mg/kg/injection. Narcotic drug administration resulted in a disturbance of the patterns of food and water intake. Shortly after drug administration food intake was stimulated, followed by an increased consumption of water. The patterns of food and water intake remained disturbed in animals showing self-injecting behavior. With amphetamine both the quantity of food and the frequency of eating were reduced. These effects were observed only temporarily in animals tested without prior forced injections. The present results indicate that measuring the reinforcing efficacy of drugs under strictly defined experimental conditions provides quantitative criteria for intravenous self-administration of drugs in rats.     

Gastrointestinal contents in fasted state and post-lipid ingestion: In vivo measurements and in vitro models for studying oral drug delivery

Lipids, either derived from food or used as drug delivery agents, can have a significant effect on orally delivered drug dissolution, absorption, and bioavailability. Despite numerous studies about fat-rich food/drug interactions, there is still an incomplete understanding of the influence of ingested lipids on oral bioavailability, and a lack of a general in vitro model that is able to predict a priori the in vivo performance of drug-lipid systems. In order to determine the impact of lipid and lipid digestion on drug dissolution and absorption, the choice of a bio-relevant in vitro model is the first and crucial point. A suitable in vitro model should include a medium that mimics as much as possible the gastrointestinal (GI) tract contents after food intake. The goal of this review is to provide an updated overview of (i) in vivo measurements examining stomach and intestine contents in fasted and fed states and (ii) the wide variety of bio-relevant media used in dissolution testing and in vitro lipid digestion studies. These approaches are compared and discussed in light of their capability to model physiological and physicochemical properties of GI tract contents in the fasted and fed states, and in particular when the lipid digestion process occurs.     

Intestinal secretion of intravenous talinolol is inhibited by luminal R-verapamil.

OBJECTIVE: To examine the secretion of the beta1-adrenergic receptor antagonist talinolol into the small intestine during its intravenous administration and to show the relevance of the P-glycoprotein-modulating drug verapamil for this secretory transport mechanism in humans. METHODS: In six healthy volunteers the intestinal steady-state perfusion technique (triple lumen tubing system) was used for measuring the appearance of talinolol within the small intestine while the drug was infused intravenously. During four of the seven perfusions performed, the perfusion fluid was changed from a verapamil-free solution and talinolol appearance was measured while a R-verapamil-containing solution (565 micromol/L) was perfused. RESULTS: Talinolol was transported into the intestinal lumen up to a concentration gradient between lumen and blood of about 5.5:1. While perfusing the small intestine with a verapamil-free solution, the intestinal secretion rate of talinolol ranged from 1.94 to 6.62 microg/min per 30 cm length of the intestine (median values). Perfusion of a R-verapamil-containing perfusion fluid resulted in lower secretion rates (0.59 to 3.71 microg/30 cm x min), corresponding to 29% to 56% of the values obtained without verapamil supplied intraluminally. CONCLUSION: Intravenously administered talinolol is actively secreted into the human small intestine. This secretion is reduced by the intraluminal supply of the P-glycoprotein modulating drug R-verapamil. This gives further rationale for P-glycoprotein-mediated intestinal drug secretion as a cause for incomplete oral bioavailability and for drug interactions during intestinal absorption.     

Pluronic block copolymers as novel polymer therapeutics for drug and gene delivery.

Pluronic block copolymers are found to be an efficient drug delivery system with multiple effects. The incorporation of drugs into the core of the micelles formed by Pluronic results in increased solubility, metabolic stability and circulation time for the drug. The interactions of the Pluronic unimers with multidrug-resistant cancer cells result in sensitization of these cells with respect to various anticancer agents. Furthermore, the single molecular chains of copolymer, unimers, inhibit drug efflux transporters in both the blood-brain barrier and in the small intestine, which provides for the enhanced transport of select drugs to the brain and increases oral bioavailability. These and other applications of Pluronic block copolymers in various drug delivery and gene delivery systems are considered.     

Gastrointestinal absorption of recombinant hirudin-2 in rats

To investigate the absorption of recombinant hirudin-2 (rHV2) after oral administration to rats and its possible absorption mechanism, a series of experiments were carried out. The degradation of (125)I-rHV2 in the luminal contents and variant mucosal subcellular fractions, as well as the effect of degradation inhibition of some adjuvant was investigated. The bioavailability of rHV2, with or without degradation inhibitor after oral administration to rats was estimated, whereas the in situ loop test and everted sac experiment were also conducted to understand more about the gastrointestinal absorption of rHV2 in rats. It was demonstrated that the rHV2 was not stable in the luminal contents and subfraction of the intestinal mucosa. Some enzyme inhibitor, such as bacitracin or casein, could inhibit the degradation to certain degrees. The intact rHV2 molecules were found in the rat plasma after oral administration, and the bioavailability varies obviously, dependent on the analytical method. Some of the enzyme inhibitor could enhance the rHV2 oral absorption. There is no site difference on rHV2 absorption in different segments of small intestine. The possible transport mechanism of rHV2 across the gastrointestinal tract is concerned with the endocytosis process.     

The impact of DeltaG on the oral bioavailability of low bioavailable therapeutic agents

Low oral bioavailability continues to drive research toward identifying novel approaches to enhance drug delivery. Over the past few years, emphasis on the use of absorption enhancers has been overwhelming despite their major adverse effects. Zonula occludens toxin (Zot) was recently established as a safe and effective absorption enhancer, reversibly opening the tight junctions for hydrophilic markers and hydrophobic drugs across the small intestine and the blood brain barrier. DeltaG, the biologically active fragment of Zot, was isolated and shown to increase the in vitro transport and in vivo absorption of paracellular markers. The objective of this study was to examine the effect of DeltaG on the oral bioavailability of low bioavailable therapeutic agents. Jugular vein cannulated Sprague-Dawley rats were randomly assigned to receive the following treatments intraduodenally (ID): [(3)H]cyclosporin A, [(3)H]ritonavir, [(3)H]saquinavir, or [(3)H]acyclovir at (120 microCi/kg) alone, with protease inhibitors (PIs), or with DeltaG (720 microg/kg)/PI. Serial blood samples were collected, and plasma was analyzed for radioactivity. After ID administration with DeltaG/PI, C(max) significantly (p < 0.05) increased over a range of 197 to 5700%, whereas area under the plasma concentration time curve displayed significant increases extending over a range of 123.8 to 4990.3% for the investigated drugs. DeltaG significantly increased the in vivo oral absorption of some low bioavailable drugs in the presence of PI. This study suggests that DeltaG-mediated tight junction modulation, combined with metabolic protection, may be used to enhance the low oral bioavailability of certain drugs when administered concurrently.     

Oral colon-specific drug delivery for bee venom peptide: development of a coated calcium alginate gel beads-entrapped liposome.

Colon-specific drug delivery systems (CDDSs) can be used to improve the bioavailability of protein and peptide drugs through the oral route. A novel formulation for oral administration using coated calcium alginate gel beads-entrapped liposome and bee venom peptide as a model drug has been investigated for colon-specific drug delivery in vitro. Drug release studies under conditions mimicking stomach to colon transit have shown that the drug was protected from being released completely in the physiological environment of the stomach and small intestine. The release rate of bee venom from the coated calcium alginate gel beads-entrapped liposome was dependent on the concentration of calcium and sodium alginate, the amount of bee venom in the liposome, as well as the coating. Furthermore, a human gamma-scintigraphy technique was used in vivo to determine drug delivery more precisely. The colonic arrival time of the tablets was found to be 4-5 h. The results clearly demonstrated that the coated calcium alginate gel beads-entrapped liposome is a potential system for colon-specific drug delivery.     

ALTERATIONS IN THE MOUSE CECUM AND ITS FLORA PRODUCED BY ANTIBACTERIAL DRUGS

Addition of penicillin, Terramycin, or kanamycin to the drinking water of adult mice rapidly induced in them an enlargement of the cecum. In all animals, this occurred within 12 hr after the beginning of drug administration—the effect being most pronounced with penicillin. The cecums remained enlarged and generally continued to increase in size as long as the antibacterial drugs were administered. The increase in wet weight of the cecums was due primarily to an accumulation of water in the lumens during the first 24–48 hr of drug administration. At that time, there were no detectable histological changes in any case, but the bacteriological picture differed from drug to drug. The cecums were free of bacteria in animals receiving penicillin, fusiform-shaped bacteria and bacteroides were present in those receiving Terramycin, and lactobacilli and bacteroides in those receiving kanamycin. After the initial 48 hr, an abundant and complex secondary microflora developed in all treated animals, its composition being characteristic for each type of antibacterial drug. When penicillin was administered for 2 wk, the cecal weights and microbial populations did not return to normal levels for over 14 days after discontinuance of the drug. This recovery period could be shortened to 10 days by giving the mice food contaminated with cecal homogenates prepared from normal animals. A period of 7 or 8 days was required for the cecal weights and microflora to reach normal levels when the administration of penicillin lasted only 24 hr; this period could not be shortened by giving the animals contaminated food. The effects of drugs on the size and bacterial contents of the cecum have been discussed in the light of earlier findings concerning the characteristics of the huge cecums uniformly found in germfree mice. Taken together, these observations support the hypothesis that certain elements of the intestinal microflora—not yet completely identified—play an essential role in maintaining the integrity of the water-transport mechanism in the intestinal epithelium.