Objectives This review discusses the limitations and applications of the everted gut sac model in studying drug absorption, metabolism, and interaction.



Key findings  The mechanism of drug absorption, interaction and the effect of factors such as age, sex, species, chronic therapy, and disease state on drug absorption have been summarized. The experimental conditions and their effects on the outcomes of trials have been discussed also.



Summary  The everted sac model is an efficient tool for studying in-vitro drug absorption mechanisms, intestinal metabolism of drugs, role of transporter in drug absorption, and for investigating the role of intestinal enzymes during drug transport through the intestine.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.2042-7158.2011.01391.x

Everted gut sac model as a tool in pharmaceutical research: limitations and applications

Publisher Summary Quinolone agents exhibit a bicyclic aromatic core, containing a carbon at the 8th position, yielding a true quinolone, or a nitrogen, and provide a ring system technically termed as naphthyridone. In common usage, both quinolone and naphthyridone structures are encompassed in the class descriptor “quinolone antibacterial agents.” The first generation quinolone compounds generally displayed increased Gram-negative activity over nalidixic acid, but lacked useful activity against Gram-positive cocci, Pseudomonas aeruginosa, and anaerobes. They were, however, generally well absorbed after oral administration and attained high concentrations in the urinary tract, making them useful therapeutically for treatment of urinary tract infections. In the second-generation quinolones, the piperazine ring remains relatively undisturbed, except for alkylation on the distal nitrogen or, less frequently, on the ring carbons. The second-generation compounds are characterized by good to excellent Gram-negative activity, with ciprofloxacin exhibiting the strongest Gram-negative spectrum. The third- and fourth-generation quinolones are characterized by increased structural novelty and complexity, which has resulted in new and useful characteristics. Clinafloxacin, sitafloxacin, and BAY y 3118, all of which bear a chlorine atom at C-8, are among the most potent broad-spectrum agents that have been in the development, and are the only compounds that exhibit Gram-negative activity superior to that of ciprofloxacin. These compounds, with the exception of pazufloxacin, show improved activity against S. pneumoniae compared to ciprofloxacin. The most potent of these agents are gemifloxacin and BAY y 3118, followed by clinafloxacin, sitafloxacin, moxifloxacin, and trovafloxacin.

Chemistry and Mechanism of Action of the Quinolone Antibacterials

Membrane transporters are major determinants for the pharmacokinetic, safety and efficacy behavior of drugs. Available technologies to study function and structure of transport proteins has strongly stimulated research in transporter biology and uncovered their importance for the drug discovery and development process, especially for drug absorption and disposition. Physiological transport systems are investigated as potential ferries to improve drug absorption and membrane permeation and to achieve organ-specific drug action. In particular, the bile acid transport systems in the liver and the small intestine and the oligopeptide transporters are of significant importance for molecular drug delivery.

Transporters, Trojan horses and therapeutics: suitability of bile acid and peptide transporters for drug delivery.

Antibiotic-responsive diarrhea (ARD) is an idiopathic syndrome causing chronic diarrhea in young, large-breed dogs Why antibiotics are effective in controlling diarrhea is not understood, and whether small intestinal bacterial numbers are truly increased is now doubted, but previous focus on the condition being small intestinal bacterial overgrowth has hampered the understanding of this condition The name ARD simply defines the condition, and studies are now looking at the interaction of small intestinal bacteria and the mucosa to try to understand why it occurs

Antibiotic-responsive diarrhea in small animals.

Synthesis of lipophilic dimeric C-7/C-7-linked ciprofloxacin and C-6/C-6-linked levofloxacin derivatives. Versatile in vitro biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or antimycobacterial agents.

We newly synthesized a pivaloyloxymethyl ester of ofloxacin (OFLX-PVM) as prodrug in order to avoid the chelate formation between new quinolone and metal cations such as Al3+, Mg2+, Ca2+, or Fe2+ in the gastrointestinal tract. This compound was rapidly hydrolyzed in an incubation experiment by 43% in plasma, by 92% in small intestinal mucosal homogenates, and by 97% in liver homogenates during 0.5 h incubation, but was resistant to hydrolysis by pancreatic enzymes. In everted gut sac experiments, this compound was efficiently absorbed even in the presence of aluminium ion, whereas the absorption of ofloxacin (OFLX) was decreased significantly by the presence of aluminium ion. Minimal inhibitory concentration (MIC) values of OFLX-PVM were far higher than OFLX. Effects of aluminium hydroxide on the oral bioavailability of OFLX and OFLX-PVM were investigated in rabbits. The area under the plasma concentration-versus-time curve from zero to 24 h (AUC0-24h) following oral administration of OFLX was decreased significantly by 47.6% by combined administration with aluminium hydroxide, but AUC0-24h values of OFLX-PVM coadministered with and without aluminium hydroxide were similar to that of OFLX alone. These observations indicate that this new compound is likely to offer a prodrug for avoidance of interaction between new quinolone and metal cations.

Effects of aluminium-containing antacid on bioavailability of ofloxacin following oral administration of pivaloyloxymethyl ester of ofloxacin as prodrug

We investigated a newly synthesized conjugate of ursodeoxycholic acid with para-aminobenzoic acid (PABA) to determine its suitability to evaluate enteric bacteria. This compound, PABA-UDCA, is deconjugated by cholylglycine hydrolase to release free PABA whereas it is completely resistant to deconjugation by pancreatic and intestinal mucosal enzymes. In bacteriological experiments, almost all of the microorganisms which split glycocholic acid deconjugated this compound. In animal experiments, urinary excretions of PABA were measured for 6 hours following oral administration of 10 mg PABA-UDCA. Ten control rats excreted 338.5±43.8μg (mean ± SD) of PABA; 10 rats with intestinal bacterial overgrowth due to enteric stagnant loops excreted more (673.6±222.1μgp<0.01), whereas 10 rats in each of 8 groups with intestinal antisepsis by oral administration of various antibiotics excreted significantly less (p<0.001) (ampicillin + doxycycline + fradiomycin: 18.3±16.7, polymixin B + tinidazole: 14.0±8.0, polymixin B: 224.9±74.3, tinidazole: 42.7±27.3, kanamycin: 50.3±18.2, clindamycin: 57.4±23.3, vancomycin: 70.4±27.0, and paromomycin: 160.4±51.9μg). These observations indicate that this compound is likely to offer a simple and rapid method for evaluation of intestinal microorganisms without the use of radioisotopes or expensive, special apparatus.

A new simple test for evaluation of intestinal bacteria.

胸腔鏡手術の普及に伴い,術前CTガイド下マーキングを施行する機会が増えている.今回,われわれはCTガイド下マーキング中に発症した空気塞栓症の1例を経験したので報告する.症例は71歳,男性.左肺S9の腫瘤に対し,術直前CTガイド下マーキングを施行した.マーキング直後,咳漱と共に意識を消失した. CTで左室と胸部大動脈内に空気像を認め空気塞栓症と診断した.直ちに頭低位としICUへ入室したが,まもなく意識は回復した.左片麻痺を生じていたが,約1時間後完全に回復した.また,心電図上STの上昇があったが, 5分後には消失した.後遺症もなく5日後に胸腔鏡補助下肺部分切除術を施行し,術後17日目に退院した. CTガイド下マーキング時の空気塞栓症は極めて稀な合併症であるが,このことを十分念頭に置いて施行すべきである.

A case of air embolism complicated during ct guided marking of a pulmonary mass

A newly synthesized conjugate of 7-hydroxy-3-O-phosphonocholic acid (ursodeoxycholic acid monophosphate) with 5-aminosalicylic acid (5-ASA-UDCA monophosphate) was investigated to determine its suitability for the evaluation of enteric bacteria. This compound, 5-ASA-UDCA monophosphate, was efficiently deconjugated by cholylglycine hydrolase to release 5-ASA, whereas it was completely resistant to deconjugation by pancreatic and intestinal mucosal enzymes. In everted gut sac experiments, 5-ASA-UDCA monophosphate was not actively absorbed from any part of the small intestine. In animal experiments, urinary excretions of N-acetyl-5-ASA (Ac-5ASA) were measured for 24 h following the oral administration of 20 mg of 5-ASA-UDCA monophosphate. Control rats excreted 276.3 +/- 89.0 micrograms (mean +/- S.E.) of Ac-5ASA, whereas the rats with intestinal bacterial overgrowth excreted more (1224.1 +/- 231.5 micrograms; p < 0.01). These basic studies indicate that this compound is likely to offer a simple method for the evaluation of microbial overgrowth without the use of radioisotopes or expensive, special apparatus.

Basic Studies on 5-(7-Hydroxy-3-O-phosphonocholyl)aminosalicylic Acid for the Evaluation of Microbial Overgrowth

Hydrolysis of ursodeoxycholyl-p-aminobenzoic acid (PABA-UDCA), a synthetic bile acid conjugate used for the evaluation of the activity of intestinal bacterial growth, was studied with pancreatic enzymes, carboxypeptidase A, carboxypeptidase B, trypsin α-chymotrypsin, cholylglycine hydrolase, liver homogenate, small intestinal homogenates, and plasma, in comparison with the hydrolysis of glycocholic acid, ursodeoxycholyl-L-leucine (L-Leu-UDCA), and ursodeoxycholyl-L-lysine (L-Lys-UDCA). PABA-UDCA was specifically cleaved by bacterial cholylglycine hydrolase to ursodeoxycholic acid and para-aminobenzoic acid (PABA), but not by pancreatic enzymes. L-Leu-UDCA was cleaved by pancreatic enzymes, carboxypeptidase A, and cholylglycine hydrolase. L-Lys-UDCA was cleaved by pancreatic enzymes, carboxypeptidase B, and cholylglycine hydrolase. The small amount of glycocholic acid was cleaved by pancreatic enzymes and carboxypeptidase A and B, and cholylglycine hydrolase hydrolyzed glycocholic acid completely. In everted gut sac experiments, PABA-UDCA was absorbed by active transport in the rat terminal ileum, and the same rate of PABA was absorbed by passive diffusion in the four segments of the rat small intestine. These observations indicate that PABA-UDCA test can evaluate the activity of small intestinal bacterial growth.

Makoto Takahashi

Papers

Effects of aluminium-containing antacid on bioavailability of ofloxacin following oral administration of pivaloyloxymethyl ester of ofloxacin as prodrug

A new simple test for evaluation of intestinal bacteria.

A case of air embolism complicated during ct guided marking of a pulmonary mass

Basic Studies on 5-(7-Hydroxy-3-O-phosphonocholyl)aminosalicylic Acid for the Evaluation of Microbial Overgrowth

Hydrolysis and absorption of a conjugate of ursodeoxycholic acid with para-aminobenzoic acid.