Analysis of models for determining intestinal wall permeabilities

Amidon, Gordon L.; Kou, Jim H.; Elliott, Richard L.; Lightfoot, E. N.

doi:10.1002/jps.2600691204

Cited by 101 publications

(58 citation statements)

References 4 publications

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“…This was done for a recently published dataset of 11 drugs whose in vivo absorption was measured in different segments of the human SI during single-pass open perfusion experiments (4,5). Regional P eff values were originally derived by Lennernäs by re-arranging the reported absorption data to a parallel tube model (4,5,12,18). Selection of this model was based on its ability to describe the hydrodynamics of the absorption process during open and/ or semi-open single-pass perfusion experiments (12,18), as shown in Eq.…”

Section: Analysis Of the Differences In Regional Intestinal Permeabilitymentioning

confidence: 99%

“…jejunal vs ileal. It is worth noting that P eff,int is not intended to represent pure membrane permeability (P m ) (50); instead, as for P eff , P eff,int is a lumped parameter involving several permeation mechanisms (2,(17)(18)(19).…”

Section: Analysis Of the Differences In Regional Intestinal Permeabilitymentioning

confidence: 99%

“…mechanisms involved, i.e. unstirred water layer (UWL) permeation, transcellular permeation, paracellular permeation and/or carried-mediated absorption/efflux (2,(17)(18)(19). In addition, jejunal P eff can be affected by the experimental conditions and the physiological factors that the drug might encounter during its passage through the intestinal membrane in the upper jejunum (3,12,20).…”

Section: Introductionmentioning

confidence: 99%

“…Intestinal P eff is a time-and position-dependent parameter, and its magnitude is a function of the nature of the small-intestinal membrane and the luminal conditions (1)(2)(3)18,21). The latter is of special interest in the cases where jejunal P eff alone might not necessarily explain the drug absorption in certain regions of the human GI tract.…”

Section: Introductionmentioning

confidence: 99%

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Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Olivares‐Morales

Lennernäs

Aarons

et al. 2015

AAPS J

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Abstract. Regional intestinal effective permeability (P eff ) values are key for the understanding of drug absorption along the whole length of the human gastrointestinal (GI) tract. The distal regions of the GI tract (i.e. ileum, ascending-transverse colon) represent the main sites for GI absorption when there is incomplete absorption in the upper GI tract, e.g. for modified release formulations. In this work, a new and pragmatic method for the estimation of (passive) intestinal permeability in the different intestinal regions is being proposed, by translating the observed differences in the available mucosal surface area along the human GI tract into corrections of the historical determined jejunal P eff values. These new intestinal P eff values or Bintrinsic^P eff (P eff,int ) were subsequently employed for the prediction of the ileal absorption clearance (CL abs,ileum ) for a set of structurally diverse compounds. Additionally, the method was combined with a semimechanistic absorption PBPK model for the prediction of the fraction absorbed (f abs ). The results showed that P eff,int can successfully be employed for the prediction of the ileal CL abs and the f abs . P eff,int also showed to be a robust predictor of the f abs when the colonic absorption was allowed in the PBPK model, reducing the overprediction of f abs observed for lowly permeable compounds when using the historical P eff values. Due to its simplicity, this approach provides a useful alternative for the bottom-up prediction of GI drug absorption, especially when the distal GI tract plays a crucial role for a drug's GI absorption.KEY WORDS: intestinal permeability; oral drug absorption; physiologically based pharmacokinetic modelling.

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Section: Analysis Of the Differences In Regional Intestinal Permeabilitymentioning

confidence: 99%

Section: Analysis Of the Differences In Regional Intestinal Permeabilitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Olivares‐Morales

Lennernäs

Aarons

et al. 2015

AAPS J

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“…Under most conditions, NWF is negative value, which indicates the intestinal lumen would absorb the water. Only when the high osmotic solution is administered, the intestinal lumen secretes the water and UWF is positive value [17,19,20].…”

Section: Discussionmentioning

confidence: 99%

Preparation of nobiletin in self-microemulsifying systems and its intestinal permeability in rats

Yao¹,

Lü²,

Zhou³

2008

J Pharm Pharm Sci

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-PURPOSE. The objective of this study was to prepare nobiletin self-microemulsifying drug delivery systems (SMEDDS) and investigate its intestinal transport behavior using the single-pass intestinal perfusion (SPIP) method in rat. METHODS. The characterizations of nobiletin SMEDDS were investigated. SPIP was performed in each isolated region of the small intestine (i.e. duodenum, jejunum, ileum and colon) over three concentrations of nobiletin (15, 30 and 60 µg/mL) at a flow rate of 0.2 ml/min. The concentrations of the samples were determined by HPLC and the effective permeability coefficients (P eff ) in rats were calculated. Considering the high correlation of rat P eff values with those of human, the human intestinal permeability was predicted using the Lawrence compartment absorption and transit model. The intestinal permeability of nobiletin in SMEDDS, sub-microemulsions and micelles was compared. RESULTS. The particle size and zeta potential of nobiletin SMEDDS were (28.6±0.3) nm and (-22.6±3.5) mV, respectively. The P eff in jejunum at 15 µg/mL was significantly higher than that at 60 µg/mL (p< 0.01). The P eff in colon was higher at the same concentration comparing to the other intestinal segments. Moreover, there was no statistical difference in P eff at each same concentration in jejunum, duodenum and ileum. The estimated human absorption of nobiletin for the SMEDDS dilutions was higher than that for sub-microemulsions (p<0.01) and similar to that of the micelles (p>0.05). CONCLUSIONS. Bases on the above results, the SMEDDS could enhance the intestinal permeability of the nobiletin, and may be presented as potential candidates for improving the oral absorption of the noblietin.

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In Vivo Methods for Oral Bioavailability Studies

Ruiz‐Garcia,

Bermejo

2023

Oral Bioavailability and Drug Delivery

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Analysis of models for determining intestinal wall permeabilities

Cited by 101 publications

References 4 publications

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

Preparation of nobiletin in self-microemulsifying systems and its intestinal permeability in rats

In Vivo Methods for Oral Bioavailability Studies

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