Assessment of enzymatic prodrug stability in human, dog and simulated intestinal fluids

Borde, Annika; Karlsson, Εva; Andersson, Kjell; Björhall, Karin; Lennernäs, Hans; Abrahamsson, Bertil

doi:10.1016/j.ejpb.2011.11.011

Cited by 30 publications

(38 citation statements)

References 27 publications

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“…(Lund-Pero et al, 1994) In a next step, the stability of SV was explored in three different intestinal media with levels of complexity increasing in the following order: FaSSIF, FaSSIF supplemented with pancreatin and FaHIF. (Borde et al, 2012); ("U.S. Pharmacopeial Convention," 2009) As compared to the gastric fluids, less degradation was observed ( Figure 3B). The degradation of SV to SVA was strongest in FaHIF.…”

Section: Stability Studymentioning

confidence: 79%

“…FaSSIF was prepared by dissolving SIF powder (2.24 mg/mL) in a phosphate buffer (pH 6.5). To provide the simulated fluids with hydrolyzing capacity, FaSSIF was supplemented with pancreatin (10 mg/mL) as described by Borde et al (Borde et al, 2012) After vortex mixing, this suspension was centrifuged (2.880 g) and the supernatant was used for the stability study.…”

Section: Mediamentioning

confidence: 99%

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In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

Geboers

Stappaerts

Tack³

et al. 2016

International Journal of Pharmaceutics

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Simvastatin (SV) is marketed as a lactone ester prodrug which is hydrolyzed to the active simvastatin hydroxyacid (SVA). SV is characterized by a low solubility and undergoes extensive first-pass metabolism. In this study, the influence of the upper gastrointestinal environment on the intraluminal behavior of simvastatin was investigated by a series of in vitro experiments. Dissolution, stability and two-stage dissolution tests were performed using simulated and human gastrointestinal fluids. The dissolution studies revealed a relatively slow dissolution of SV as well as conversion of SV to SVA. The hydrolysis of SV was further examined and stability studies indicated a faster conversion in gastric fluids than in intestinal fluids. These isolated phenomena were then confirmed by the more integrative two-stage dissolution studies. To estimate the predictive value of the in vitro tests, an additional in vivo study was performed in which the gastrointestinal concentration-time profiles also revealed a slow dissolution of SV and faster degradation of SV to SVA in the stomach than in the intestinal tract. However, the plasma concentrations of SV and SVA did not directly correlate with the observed gastrointestinal concentrations, suggesting that gut wall and hepatic metabolism have a greater impact on systemic exposure of SV than the intraluminal interconversion between SV and SVA.

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Section: Stability Studymentioning

confidence: 79%

Section: Mediamentioning

confidence: 99%

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

Geboers

Stappaerts

Tack³

et al. 2016

International Journal of Pharmaceutics

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“…Instability in intestinal fluids has been observed for several other ester prodrugs and is generally regarded as disadvantageous to the overall prodrug approach [2,11]. A more thorough evaluation of the concentration profiles of abiraterone and abiraterone acetate upon prodrug incubation in FaHIF during the solubility studies indicates that the concentrations of abiraterone generated by prodrug hydrolysis upon 1, 2 and 5 h of incubation were significantly higher than the solubility of abiraterone determined by incubation of abiraterone (Fig.…”

Section: Stability and Dissolution Testsmentioning

confidence: 96%

“…Borde et al proposed the use of dog intestinal fluids as an alternative to human intestinal fluids [2]. In the same study, the use of fasted state simulated intestinal fluids supplemented with pancreatin was also evaluated as a solvent system to determine ester prodrug stability; however, both in dog intestinal fluids and in the simulated fluids, degradation was found to be slow as compared to degradation in human intestinal fluids.…”

Section: Introductionmentioning

confidence: 98%

“…Being ubiquitously present in the enterocytes, they pose an important limitation in the absorption of drugs carrying an ester bond [1]. In addition to intracellular hydrolysis, several studies report on the instability of ester prodrugs in human intestinal fluids [2][3][4][5]. In view of the labile nature of ester prodrugs, assessment of stability in intestinal fluids is crucial.…”

Section: Introductionmentioning

confidence: 99%

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Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: In vitro, rat in situ and human in vivo studies

Stappaerts

Geboers

Snoeys

et al. 2015

European Journal of Pharmaceutics and Biopharmaceutics

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The aim of this study was to evaluate the intestinal disposition of abiraterone acetate, an ester prodrug of the anticancer agent abiraterone. Stability of the prodrug and solubility and dissolution characteristics of both abiraterone and abiraterone acetate were monitored in vitro. Moreover, the in vivo intraluminal concentrations of abiraterone and abiraterone acetate upon intake of one tablet of 250 mg abiraterone acetate were assessed in healthy volunteers. The intestinal absorption resulting from the intraluminal behavior of the ester prodrug was determined using the rat in situ intestinal perfusion technique with mesenteric blood sampling. Simulated and aspirated human intestinal fluids of the fasted state were used as solvent systems. Upon incubation of abiraterone acetate in human intestinal fluids in vitro, rapid hydrolysis of the prodrug was observed, generating abiraterone concentrations largely exceeding the apparent solubility of abiraterone, suggesting the existence of intestinal supersaturation. These findings were confirmed in vivo, by intraluminal sampling of duodenal fluids upon oral intake of an abiraterone acetate tablet by healthy volunteers. Rat in situ intestinal perfusion experiments performed with suspensions of abiraterone and abiraterone acetate in human intestinal fluids of the fasted state revealed significantly higher flux values upon perfusion with the prodrug than with abiraterone. Moreover, rat in situ intestinal perfusion with abiraterone acetate suspensions in simulated fluids of the fasted state in presence or absence of esterases demonstrated that increased hydrolytic activity of the perfusion medium was beneficial to the intestinal absorption of abiraterone. In conclusion, the rapid hydrolysis of abiraterone acetate in the intraluminal environment appears to result in fast and extensive generation of abiraterone supersaturation, creating a strong driving force for abiraterone absorption.

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A Novel Strategy for ADME Screening of Prodrugs: Combined Use of Serum and Hepatocytes to Integrate Bioactivation and Clearance, and Predict Exposure to Both Active and Prodrug to the Systemic Circulation

Hoppe

Hewitt²,

Buchstaller

et al. 2014

Journal of Pharmaceutical Sciences

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Assessment of enzymatic prodrug stability in human, dog and simulated intestinal fluids

Cited by 30 publications

References 27 publications

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

In vitro and in vivo investigation of the gastrointestinal behavior of simvastatin

Rapid conversion of the ester prodrug abiraterone acetate results in intestinal supersaturation and enhanced absorption of abiraterone: In vitro, rat in situ and human in vivo studies

A Novel Strategy for ADME Screening of Prodrugs: Combined Use of Serum and Hepatocytes to Integrate Bioactivation and Clearance, and Predict Exposure to Both Active and Prodrug to the Systemic Circulation

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