A Residence-Time Distribution Analysis of the Hydrodynamics within the Intestine in Man during a Regional Single-pass Perfusion with Loc-I-Gut: In-vivo Permeability Estimation

Lennernäs, Hans; Lee, I-Der; Fagerholm, Urban; Amidon, Gordon L.

doi:10.1111/j.2042-7158.1997.tb06092.x

Cited by 42 publications

(29 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). a BCS classification from reference (4) b Observed f abs data from reference (33) Despite this simplification, P eff , as it is, has been an effective predictor of both the rate and extent the GI absorption (2,16,61). This discrepancy can be explained by the following differential equation that describes the drug absorption from the SI (assuming the SI as single compartment) (1,2):…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

“…In the double-balloon technique, the drug is single-pass perfused in solution to conscious human volunteers employing a multilumen tube. The reader is referred to the following references for more details about the clinical procedure, the data analysis and the doubleballoon technique (1,2,(13)(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…When the perfusate (NuTRIflex) reached the intestinal lumen it was immediately diluted according to the well-mixed hydrodynamics (28). The concentrations of the lipidic components in the NuTRIflex solution upon entry in the jejunum were therefore calculated for each time interval under the assumption that dilution took place immediately upon entering the small intestine and that no degradation or absorption occurred.…”

Section: Perfusate Datamentioning

confidence: 99%

A Clinical Single-Pass Perfusion Investigation of the Dynamic in Vivo Secretory Response to a Dietary Meal in Human Proximal Small Intestine

et al. 2006

Self Cite

View full text Add to dashboard Cite

show abstract

“…Intestinal P eff was calculated according to a well-mixed tank model (Lennernäs et al, 1997) (eq. 3):…”

Section: Stereoselective Metabolism Of R/s-verapamil In Pigsmentioning

confidence: 99%

Different Effects of Ketoconazole on the Stereoselective First-Pass Metabolism of R/S-Verapamil in the Intestine and the Liver: Important for the Mechanistic Understanding of First-Pass Drug-Drug Interactions

Thörn¹,

Hedeland²,

Bondesson³

et al. 2009

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:In this acute study a pig jejunal intestinal perfusion model with multiple plasma sampling sites and three different administration routes was used to investigate the quantitative contribution of the intestine versus liver to the first-pass extraction of each enantiomer of verapamil (VER). A subclinical dose of ketoconazole (8 mg) was coadministered in the perfusion solution to selectively inhibit gut wall CYP3A. Both enantiomers of VER and its main metabolite norverapamil (NOR) as well as the inhibitor ketoconazole were quantified in all plasma compartments by liquid chromatographytandem mass spectrometry. The overall first-pass metabolic extraction of VER and the metabolite NOR was shown to be stereoselective with the S-isomer being more extensively extracted. For VER the ratio of R-enantiomer to S-enantiomer was greater in the hepatic vein than in the portal vein (ϳ2.2 versus 1.4), indicating that the stereoselective metabolism of VER in pigs mainly occurs on the first pass through the liver and not in the intestine. Ketoconazole increased the area under the curve from time 0 to 6 h and C max of R-and S-VER at least 3-fold in the portal vein, most likely explained by inhibition of gut wall metabolism. Conversely, hepatic extraction was increased because the effect of gut wall metabolism was not observed at the peripheral sampling sites. In conclusion, this study provided novel and more direct information on the contribution of the intestine and the liver, respectively, to the overall first-pass extraction of racemic VER.

show abstract

A Residence-Time Distribution Analysis of the Hydrodynamics within the Intestine in Man during a Regional Single-pass Perfusion with Loc-I-Gut: In-vivo Permeability Estimation

Cited by 42 publications

References 15 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

A Clinical Single-Pass Perfusion Investigation of the Dynamic in Vivo Secretory Response to a Dietary Meal in Human Proximal Small Intestine

Different Effects of Ketoconazole on the Stereoselective First-Pass Metabolism of R/S-Verapamil in the Intestine and the Liver: Important for the Mechanistic Understanding of First-Pass Drug-Drug Interactions

Contact Info

Product

Resources

About