A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential

Zhu, Chengyue; Jiang, Lan Ying; Chen, Teng‐Man; Hwang, Kwang Woo

doi:10.1016/s0223-5234(02)01360-0

Cited by 320 publications

(222 citation statements)

References 30 publications

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“…3 and 4) revealed the blunting effect due to drug reabsorption, or the factor (1-F abs ), where F abs or fraction absorbed is k a /(k a ϩ k g ) [where k g is the luminal degradation constant that comprises gastrointestinal transit and degradation] (Lin et al, 1999;Pang, 2009, 2010). The F abs term has been reported to be highly correlated to the permeability of drug, P app (Zhu et al, 2002;Corti et al, 2006;Kadono et al, 2010). Apical secretion mediated via the CL int,sec,I was nullified when the fraction absorbed ϳ1, rendering the conclusion that F I is affected more by CL int,met,I and not so much by CL int,sec,I Pang, 2009, 2010;Chow and Pang, 2013).…”

Section: Theoretical: the Intestinal Flow Modelsmentioning

confidence: 99%

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Pang

Chow

2012

Drug Metab Dispos

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ABSTRACT:Physiologically based pharmacokinetic (PBPK) models for the intestine, comprising of different flow rates perfusing the enterocyte region, were revisited for appraisal of flow affects on the intestinal availability (F I ) and, in turn, the systemic availability (F sys ) and intestinal versus liver contribution to the first-pass effect during oral drug absorption. The traditional model (TM), segregated flow model (SFM), and effective flow (Q Gut ) model stipulate that 1.0, ϳ0.05 to 0.3, and <0.484؋ of the total intestinal flow, respectively, reach the enterocyte region that houses metabolically active and transporter-enriched enterocytes. The fractional flow rate to the enterocyte region (f Q ), when examined under varying experimental conditions, was found to range from 0.024 to 0.2 for the SFM and 0.065 to 0.43 for the Q Gut model. Appraisal of these flow intestinal models, when used in combination with whole-body PBPK models, showed the ranking as SFM < Q Gut model < TM in the description of F I , and the same ranking existed for the contribution of the intestine to first-pass removal. However, the ranking for the predicted contribution of hepatic metabolism, when present, to firstpass removal was the opposite: SFM > Q Gut model > TM. The findings suggest that the f Q value strongly influences the rate of intestinal metabolism (F I and F sys ) and indirectly affects the rate of liver metabolism due to substrate sparing effect. Thus, the f Q value in the intestinal flow models pose serious implications on the interpretation of data on the first-pass effect and oral absorption of drugs.

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Section: Theoretical: the Intestinal Flow Modelsmentioning

confidence: 99%

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Pang

Chow

2012

Drug Metab Dispos

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“…The extent of gastro-intestinal absorption is one of the key properties for drugs intended for oral administration [1][2][3][4][5][6]. Of many factors that govern intestinal absorption of a compound, permeability is often tested in vitro by means of cell-based assays such as the Caco-2 assay [2][3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…Of many factors that govern intestinal absorption of a compound, permeability is often tested in vitro by means of cell-based assays such as the Caco-2 assay [2][3][4][5][6][7][8]. While the Caco-2 assay is the gold standard for in vitro permeability assessment, interpretation of the results from such assays needs careful attention due to high lab-to-lab variability [6,8].…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays

Lee

Zgair

Taha

et al. 2017

European Journal of Pharmaceutics and Biopharmaceutics

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In this study, Caco-2 permeability results from different laboratories were compared. Six different sets of apparent permeability coefficient (Papp) values reported in the literature were compared to experimental Papp obtained in our laboratory. The differences were assessed by determining the root mean square error (RMSE) values between the datasets, which reached levels as high as 0.581 for the training set compounds, i.e. ten compounds with known effective human permeability (Peff). The consequences of these differences in Papp for prediction of oral drug absorption were demonstrated by introducing the Papp into the absorption and pharmacokinetics simulation software application GastroPlus TM for prediction of the fraction absorbed (Fa) in humans using calibrated "user-defined permeability models". The RMSE were calculated to assess the differences between the simulated Fa and experimental values reported in the literature. The RMSE for Fa simulated with the permeability model calibrated using experimental Papp from our laboratory was 0.128. When the calibration was performed usingPapp from literature datasets, the RMSE values for Fa were higher in all cases except one. This study shows quantitative lab-to-lab variability of Caco-2 permeability results and the potential consequences this can have in the use of these results for predicting intestinal absorption of drugs.

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“…The artificial membrane immobilized on a filter is placed between a donor and acceptor compartments (22). Recent studies have described numerous tissuespecific methods that predict the gastrointestinal absorption (23)(24)(25)(26), the penetration through the blood-brain barrier (27)(28)(29) or the barrier function of human skin (30). Our results revealed that modified PAMAM dendrimer with TAT peptide has more capability in the transition of the DNA plasmid through the artificial membrane, as the highest expression of the H5 gene was observed from the delivery system of TAT-conjugated dendrimer compared to the native dendrimer.…”

Section: Discussionmentioning

confidence: 99%

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery

et al. 2016

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-PURPOSE:In order to enhance cellular uptake and to facilitate transdermal delivery of DNA vaccine, polyamidoamine (PAMAM) dendrimers conjugated with HIV transactivator of transcription (TAT) was developed. METHODS: First, the plasmid DNA (pIRES-H5/GFP) nanoparticle was formulated using PAMAM dendrimer and TAT peptide and then characterized for surface charge, particle size, DNA encapsulation and protection of the pIRES-H5/GFP DNA plasmid to enzymatic digestion. Subsequently, the potency of the TATconjugated dendrimer for gene delivery was evaluated through in vitro transfection into Vero cells followed by gene expression analysis including western blotting, fluorescent microscopy and PCR. The effect of the TAT peptide on cellular uptake of DNA vaccine was studied by qRT-PCR and flow cytometry. Finally, the ability of TAT-conjugated PAMAM dendrimer for transdermal delivery of the DNA plasmid was assessed through artificial membranes followed by qRT-PCR and flow cytometry. RESULTS: TAT-conjugated PAMAM dendrimer showed the ability to form a compact and nanometre-sized polyplexes with the plasmid DNA, having the size range of 105 to 115 nm and a positive charge of +42 to +45 mV over the N/P ratio of 6:1(+/-). In vitro transfection analysis into Vero cells confirms the high potency of TAT-conjugated PAMAM dendrimer to enhance the cellular uptake of DNA vaccine. The permeability value assay through artificial membranes reveals that TAT-conjugated PAMAM has more capacity for transdermal delivery of the DNA compared to unmodified PAMAM dendrimer (P<0.05). CONCLUSIONS: The findings of this study suggest that TAT-conjugated PAMAM dendrimer is a promising non-viral vector for transdermal use.

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A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential

Cited by 320 publications

References 30 publications

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery

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A comparative study of artificial membrane permeability assay for high throughput profiling of drug absorption potential

Cited by 320 publications

References 30 publications

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGutModel

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and QGutModel

Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery

Contact Info

Product

Resources

About

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel

Commentary: Theoretical Predictions of Flow Effects on Intestinal and Systemic Availability in Physiologically Based Pharmacokinetic Intestine Models: The Traditional Model, Segregated Flow Model, and Q_GutModel