Improved analysis of bile acids in tissues and intestinal contents of rats using LC/ESI-MS

Hagio, Masahito; Matsumoto, Megumi; Fukushima, Michihiro; Hara, Hiroshi; Ishizuka, Satoshi

doi:10.1194/jlr.d800041-jlr200

Cited by 137 publications

(109 citation statements)

References 29 publications

(23 reference statements)

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“…17) In addition, the DA rats showed more severe colitis symptoms than did the WKAH rats. 38) DCA has induced cytotoxicity, oxidant production, and alterations of barrier integrity.…”

Section: Discussionmentioning

confidence: 99%

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Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Iwaya

Fujii

Hagio

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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“…17) In addition, the DA rats showed more severe colitis symptoms than did the WKAH rats. 38) DCA has induced cytotoxicity, oxidant production, and alterations of barrier integrity.…”

Section: Discussionmentioning

confidence: 99%

“…Each BA concentration was measured as described in our previous report. 17) Briefly, the ethanol extract of freeze-dried feces was evaporated and dissolved in methanol. BAs in the solution were purified by solid extraction with an HLB cartridge (Waters, Milford, MA, USA) based on the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Iwaya

Fujii

Hagio

et al. 2013

Bioscience, Biotechnology, and Biochemistry

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“…The D50 values of the particle size distributions of these nanosuspensions and microsuspensions were 0.13 µm and 16 µm for cilostazol and 0.15 µm and 7 µm for danazol, respectively. The toxicokinetic study in rats was conducted in the nonfasted state, and Hagio et al 37) reported that the concentration of bile micelles was approximately 9-17 mM in the jejunum and 15-25 mM in the ileum in nonfasted rats. Hence, FeSSIF, which contains 15 mM of bile micelles (sodium taurocholate), was used as a test medium in the in vitro dissolution study.…”

Section: Application Of Wet Media Milling With 05% Hpmc (3 Cp)-05% mentioning

confidence: 99%

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

Komasaka¹,

Fujimura

Tagawa

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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The present study aimed to develop a practical method for preparing nanosuspension formulations of poorly water-soluble compounds for enhancing oral absorption in toxicology studies in the discovery stage. To obtain a suitable nanosuspension formulation for the intended purpose, formulations were optimized with a focus on the following characteristics: i) containing a high drug concentration, ii) consisting of commonly used excipient types in proper quantities for toxicology studies, iii) having long-term stability, and iv) having versatility for use with diverse compounds. Test compounds were milled with various excipients by wet media milling methods using a mixer mill (10 mg/batch) and a rotation/revolution mixer (0.5 g/batch). As a result, 100 mg/mL nanosuspensions of all 11 test compounds could be prepared with an optimized dispersing agent, 0.5% hydroxypropyl methylcellulose (HPMC) (3 cP)-0.5% Tween 80. Notably, it was found that the molecular weight of HPMC influenced not only particle size but also the stability of nanosuspensions and they were stable for 4 weeks at 5°C. The nanosuspensions increased in vitro dissolution rates and provided 3.9 and 3.0 times higher C max and 4.4 and 1.6 times higher area under the concentration-time curve from 0-24 h (AUC 0-24 h ) in rats (oral dose of 300 mg/kg) for cilostazol and danazol, respectively. In conclusion, applying a wet media milling method with the combination of HPMC of a small molecular weight and Tween 80 as a dispersing agent, nanosuspensions can be practically prepared and conveniently utilized for enhancing the oral absorption of poorly water-soluble compounds in toxicology studies in the discovery stage.Key words nanosuspension; toxicology study; wet media milling; mixer mill; rotation revolution mixer; oral absorptionThe proportion of poorly water-soluble compounds among drug candidates in the discovery stage has been increasing for the past decade.1,2) Because of the poor solubility of these compounds, sufficient oral absorption is not observed in animal studies, and the evaluation of pharmacological and toxicological profiles of drug candidates has therefore become more challenging. In particular, this problem frequently occurs in toxicology studies that require high oral absorption and is now a common problem in pharmaceutical companies.3)The application of formulation technologies such as solubilizing excipients, 4) solid dispersions, 5,6) and nanosuspensions 7,8) is an attractive strategy for improving oral absorption of poorly water-soluble compounds. However, the use of solubilizing excipients and solid dispersions for toxicology studies in the discovery stage is practically limited because of toxicities of excipients and amount of drug substances for formulation studies, respectively. On the other hand, nanosuspensions have the potential to solve these problems. Because nanosuspensions can be prepared as highly drug-loaded formulations with small quantities of excipients, adverse effects caused by excipients can be avoided. 9) In addition, n...

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“…For intestinal contents, the extraction of BAs was performed as described elsewhere (Hagio et al, 2009). In brief, 100 mg (wet weight) intestinal contents, collected by flushing the intact intestinal tract, were homogenized in 2 vol of 50% (v/v) methanol.…”

Section: Methodsmentioning

confidence: 99%

Dietary Regulation of Mouse Intestinal P450 Expression and Drug Metabolism

et al. 2012

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The study was originally designed to test the hypothesis that the compensatory increase in intestinal P450 (cytochrome P450) expression in the intestinal epithelium-specific P450 reductase (CPR) knockout (IE-Cpr-null) mice was attributable to decreased metabolism of putative P450 inducers present in the diet. Thus, we determined the impact of a dietary change from regular rodent chow to a synthetic diet devoid of phytochemicals on the expression of P450 enzymes in the small intestine (SI) and liver of wild-type (WT) and IE-Cpr-null mice. The dietary change diminished expression of CYP1A, 2B, 2C, and 3A in SI and CYP2B, 2C, and 3A in liver of both WT and IE-Cpr-null mice. However, the compensatory increase in SI P450 expression still occurred in IE-Cpr-null, compared with WT, mice, on the synthetic diet. The diet change-induced decrease in P450 expression was accompanied by decreases in microsomal midazolam-hydroxylase activity in vitro and first-pass clearance of midazolam in vivo in WT mice. Further studies showed that the dietary change, but not Cpr deletion, caused large decreases in bile acid (BA) levels in plasma, liver, SI, and intestinal content and that treatment of WT mice on the synthetic diet with GW4064, a farnesoid-X-receptor agonist, restored the levels of CYP3A expression in both liver and SI to those seen in mice fed with regular chow. Taken together, these results highlight the vital role of diet in maintaining adequate expression of major drug-metabolizing P450s and their associated drug-metabolizing activities in the digestive tract and suggest potential involvement of BA signaling in the regulatory mechanisms.

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Improved analysis of bile acids in tissues and intestinal contents of rats using LC/ESI-MS

Cited by 137 publications

References 29 publications

Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Contribution of Dipeptidyl Peptidase IV to the Severity of Dextran Sulfate Sodium-Induced Colitis in the Early Phase

Practical Method for Preparing Nanosuspension Formulations for Toxicology Studies in the Discovery Stage: Formulation Optimization and <i>in Vitro</i>/<i>in Vivo</i> Evaluation of Nanosized Poorly Water-Soluble Compounds

Dietary Regulation of Mouse Intestinal P450 Expression and Drug Metabolism

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