Editorial

5 pages, 228 KiB

Open AccessEditorial

Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation

by Arik Dahan and Isabel González-Álvarez

Pharmaceutics 2021, 13(2), 272; https://doi.org/10.3390/pharmaceutics13020272 - 17 Feb 2021

Cited by 5 | Viewed by 3321

The gastrointestinal tract (GIT) can be broadly divided into several regions: the stomach, the small intestine (which is subdivided to duodenum, jejunum, and ileum), and the colon. The conditions and environment in each of these segments, and even within the segment, are dependent [...] Read more.

The gastrointestinal tract (GIT) can be broadly divided into several regions: the stomach, the small intestine (which is subdivided to duodenum, jejunum, and ileum), and the colon. The conditions and environment in each of these segments, and even within the segment, are dependent on many factors, e.g., the surrounding pH, fluid composition, transporters expression, metabolic enzymes activity, tight junction resistance, different morphology along the GIT, variable intestinal mucosal cell differentiation, changes in drug concentration (in cases of carrier-mediated transport), thickness and types of mucus, and resident microflora. Each of these variables, alone or in combination with others, can fundamentally alter the solubility/dissolution, the intestinal permeability, and the overall absorption of various drugs. This is the underlying mechanistic basis of regional-dependent intestinal drug absorption, which has led to many attempts to deliver drugs to specific regions throughout the GIT, aiming to optimize drug absorption, bioavailability, pharmacokinetics, and/or pharmacodynamics. In this Editorial we provide an overview of the Special Issue "Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation". The objective of this Special Issue is to highlight the current progress and to provide an overview of the latest developments in the field of regional-dependent intestinal drug absorption and delivery, as well as pointing out the unmet needs of the field. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

Research

Jump to: Editorial, Review

26 pages, 4834 KiB

Open AccessArticle

Development of a Hierarchical Support Vector Regression-Based In Silico Model for Caco-2 Permeability

by Giang Huong Ta, Cin-Syong Jhang, Ching-Feng Weng and Max K. Leong

Pharmaceutics 2021, 13(2), 174; https://doi.org/10.3390/pharmaceutics13020174 - 28 Jan 2021

Cited by 11 | Viewed by 2313

Abstract

Drug absorption is one of the critical factors that should be taken into account in the process of drug discovery and development. The human colon carcinoma cell layer (Caco-2) model has been frequently used as a surrogate to preliminarily investigate the intestinal absorption. [...] Read more.

Drug absorption is one of the critical factors that should be taken into account in the process of drug discovery and development. The human colon carcinoma cell layer (Caco-2) model has been frequently used as a surrogate to preliminarily investigate the intestinal absorption. In this study, a quantitative structure–activity relationship (QSAR) model was generated using the innovative machine learning-based hierarchical support vector regression (HSVR) scheme to depict the exceedingly confounding passive diffusion and transporter-mediated active transport. The HSVR model displayed good agreement with the experimental values of the training samples, test samples, and outlier samples. The predictivity of HSVR was further validated by a mock test and verified by various stringent statistical criteria. Consequently, this HSVR model can be employed to forecast the Caco-2 permeability to assist drug discovery and development. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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16 pages, 2526 KiB

Open AccessArticle

BCS Class IV Oral Drugs and Absorption Windows: Regional-Dependent Intestinal Permeability of Furosemide

by Milica Markovic, Moran Zur, Inna Ragatsky, Sandra Cvijić and Arik Dahan

Pharmaceutics 2020, 12(12), 1175; https://doi.org/10.3390/pharmaceutics12121175 - 02 Dec 2020

Cited by 26 | Viewed by 6366

Abstract

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. [...] Read more.

Biopharmaceutical classification system (BCS) class IV drugs (low-solubility low-permeability) are generally poor drug candidates, yet, ~5% of oral drugs on the market belong to this class. While solubility is often predictable, intestinal permeability is rather complicated and highly dependent on many biochemical/physiological parameters. In this work, we investigated the solubility/permeability of BCS class IV drug, furosemide, considering the complexity of the entire small intestine (SI). Furosemide solubility, physicochemical properties, and intestinal permeability were thoroughly investigated in-vitro and in-vivo throughout the SI. In addition, advanced in-silico simulations (GastroPlus^®) were used to elucidate furosemide regional-dependent absorption pattern. Metoprolol was used as the low/high permeability class boundary. Furosemide was found to be a low-solubility compound. Log D of furosemide at the three pH values 6.5, 7.0, and 7.5 (representing the conditions throughout the SI) showed a downward trend. Similarly, segmental-dependent in-vivo intestinal permeability was revealed; as the intestinal region becomes progressively distal, and the pH gradually increases, the permeability of furosemide significantly decreased. The opposite trend was evident for metoprolol. Theoretical physicochemical analysis based on ionization, pK_a, and partitioning predicted the same trend and confirmed the experimental results. Computational simulations clearly showed the effect of furosemide’s regional-dependent permeability on its absorption, as well as the critical role of the drug’s absorption window on the overall bioavailability. The data reveals the absorption window of furosemide in the proximal SI, allowing adequate absorption and consequent effect, despite its class IV characteristics. Nevertheless, this absorption window so early on in the SI rules out the suitability of controlled-release furosemide formulations, as confirmed by the in-silico results. The potential link between segmental-dependent intestinal permeability and adequate oral absorption of BCS Class IV drugs may aid to develop challenging drugs as successful oral products. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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14 pages, 2058 KiB

Open AccessArticle

Biomimetic Artificial Membrane Permeability Assay over Franz Cell Apparatus Using BCS Model Drugs

by Leonardo de Souza Teixeira, Tatiana Vila Chagas, Antonio Alonso, Isabel Gonzalez-Alvarez, Marival Bermejo, James Polli and Kênnia Rocha Rezende

Pharmaceutics 2020, 12(10), 988; https://doi.org/10.3390/pharmaceutics12100988 - 19 Oct 2020

Cited by 14 | Viewed by 3382

Abstract

A major parameter controlling the extent and rate of oral drug absorption is permeability through the lipid bilayer of intestinal epithelial cells. Here, a biomimetic artificial membrane permeability assay (Franz–PAMPA Pampa) was validated using a Franz cells apparatus. Both high and low permeability [...] Read more.

A major parameter controlling the extent and rate of oral drug absorption is permeability through the lipid bilayer of intestinal epithelial cells. Here, a biomimetic artificial membrane permeability assay (Franz–PAMPA Pampa) was validated using a Franz cells apparatus. Both high and low permeability drugs (metoprolol and mannitol, respectively) were used as external standards. Biomimetic properties of Franz–PAMPA were also characterized by electron paramagnetic resonance spectroscopy (EPR). Moreover, the permeation profile for eight Biopharmaceutic Classification System (BCS) model drugs cited in the FDA guidance and another six drugs (acyclovir, cimetidine, diclofenac, ibuprofen, piroxicam, and trimethoprim) were measured across Franz–PAMPA. Apparent permeability (Papp) Franz–PAMPA values were correlated with fraction of dose absorbed in humans (Fa%) from the literature. Papp in Caco-2 cells and Corti artificial membrane were likewise compared to Fa% to assess Franz–PAMPA performance. Mannitol and metoprolol Papp values across Franz–PAMPA were lower (3.20 × 10⁻⁷ and 1.61 × 10⁻⁵ cm/s, respectively) than those obtained across non-impregnated membrane (2.27 × 10⁻⁵ and 2.55 × 10⁻⁵ cm/s, respectively), confirming lipidic barrier resistivity. Performance of the Franz cell permeation apparatus using an artificial membrane showed acceptable log-linear correlation (R² = 0.664) with Fa%, as seen for Papp in Caco-2 cells (R² = 0.805). Data support the validation of the Franz–PAMPA method for use during the drug discovery process. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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16 pages, 4426 KiB

Open AccessArticle

Cubic Microcontainers Improve In Situ Colonic Mucoadhesion and Absorption of Amoxicillin in Rats

by Juliane Fjelrad Christfort, Antonio José Guillot, Ana Melero, Lasse Højlund Eklund Thamdrup, Teresa M. Garrigues, Anja Boisen, Kinga Zór and Line Hagner Nielsen

Pharmaceutics 2020, 12(4), 355; https://doi.org/10.3390/pharmaceutics12040355 - 14 Apr 2020

Cited by 17 | Viewed by 4173

Abstract

An increased interest in colonic drug delivery has led to a higher focus on the design of delivery devices targeting this part of the gastrointestinal tract. Microcontainers have previously facilitated an increase in oral bioavailability of drugs. The surface texture and shape of [...] Read more.

An increased interest in colonic drug delivery has led to a higher focus on the design of delivery devices targeting this part of the gastrointestinal tract. Microcontainers have previously facilitated an increase in oral bioavailability of drugs. The surface texture and shape of microcontainers have proven to influence the mucoadhesion ex vivo. In the present work, these findings were further investigated using an in situ closed-loop perfusion technique in the rat colon, which allowed for simultaneous evaluation of mucoadhesion of the microcontainers as well as drug absorption. Cylindrical, triangular and cubic microcontainers, with the same exterior surface area, were evaluated based on in vitro release, in situ mucoadhesion and in situ absorption of amoxicillin. Additionally, the mucoadhesion of empty cylindrical microcontainers with and without pillars on the top surface was investigated. From the microscopy analysis of the colon sections after the in situ study, it was evident that a significantly higher percentage of cubic microcontainers than cylindrical microcontainers adhered to the intestinal mucus. Furthermore, the absorption rate constants and blood samples indicated that amoxicillin in cubic microcontainers was absorbed more readily than when cylindrical or triangular microcontainers were dosed. This could be due to a higher degree of mucoadhesion for these particular microcontainers. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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17 pages, 1551 KiB

Open AccessArticle

Pharmacokinetic Models to Characterize the Absorption Phase and the Influence of a Proton Pump Inhibitor on the Overall Exposure of Dacomitinib

by Ana Ruiz-Garcia, Weiwei Tan, Jerry Li, May Haughey, Joanna Masters, Jennifer Hibma and Swan Lin

Pharmaceutics 2020, 12(4), 330; https://doi.org/10.3390/pharmaceutics12040330 - 07 Apr 2020

Cited by 13 | Viewed by 3191

Abstract

Introduction: Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations. Dacomitinib is taken orally once daily at 45 mg with or without [...] Read more.

Introduction: Dacomitinib is an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of metastatic non-small cell lung cancer (NSCLC) in the first line in patients with EGFR activating mutations. Dacomitinib is taken orally once daily at 45 mg with or without food, until disease progression or unacceptable toxicity occurs. Oncology patients often can develop gastroesophageal reflux disease (GERD), which may require management with an acid-reducing agent. Proton pump inhibitors (PPIs), such as rabeprazole, inhibit sodium-potassium adenosine triphosphatase (H⁺/K⁺-ATPase) pumps that stimulate acid secretion in the stomach and have a prolonged pharmacodynamic effect that extends beyond 24 h post-administration. The aim of this work was to characterize the absorption of dacomitinib via modeling with a particular interest in quantifying the impact of rabeprazole on the pharmacokinetics (PK) of dacomitinib. Materials and Methods: The pooled dataset consisted of five clinical pharmacology healthy volunteer studies, which collected serial pharmacokinetic concentration-time profiles of dacomitinib. Non-linear mixed effects modeling was carried out to characterize dacomitinib pharmacokinetics in the presence and absence of the concomitant use of a PPI, rabeprazole. Several absorption models, some more empirical, and some more physiologically based, were tested: transit compartment, first-order absorption with and without lag time, and variations of combined zero- and first-order absorption kinetics models. Results: The presence of a PPI was a significant covariate affecting the extent (F) and rate (ka) of dacomitinib absorption, as previously reported in the dedicated clinical study. A transit compartment model was able to best describe the absorption phase of dacomitinib. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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15 pages, 1979 KiB

Open AccessArticle

Segmental-Dependent Solubility and Permeability as Key Factors Guiding Controlled Release Drug Product Development

by Milica Markovic, Moran Zur, Noa Fine-Shamir, Ester Haimov, Isabel González-Álvarez and Arik Dahan

Pharmaceutics 2020, 12(3), 295; https://doi.org/10.3390/pharmaceutics12030295 - 24 Mar 2020

Cited by 15 | Viewed by 4334

Abstract

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug [...] Read more.

The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high P_eff marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol’s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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14 pages, 1110 KiB

Open AccessArticle

Regional Intestinal Drug Permeability and Effects of Permeation Enhancers in Rat

by David Dahlgren, Maria-Jose Cano-Cebrián, Tobias Olander, Mikael Hedeland, Markus Sjöblom and Hans Lennernäs

Pharmaceutics 2020, 12(3), 242; https://doi.org/10.3390/pharmaceutics12030242 - 08 Mar 2020

Cited by 13 | Viewed by 4238

Abstract

Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal [...] Read more.

Sufficient colonic absorption is necessary for all systemically acting drugs in dosage forms that release the drug in the large intestine. Preclinically, colonic absorption is often investigated using the rat single-pass intestinal perfusion model. This model can determine intestinal permeability based on luminal drug disappearance, as well as the effect of permeation enhancers on drug permeability. However, it is uncertain how accurate the rat single-pass intestinal perfusion model predicts regional intestinal permeability and absorption in human. There is also a shortage of systematic in vivo investigations of the direct effect of permeation enhancers in the small and large intestine. In this rat single-pass intestinal perfusion study, the jejunal and colonic permeability of two low permeability drugs (atenolol and enalaprilat) and two high-permeability ones (ketoprofen and metoprolol) was determined based on plasma appearance. These values were compared to already available corresponding human data from a study conducted in our lab. The colonic effect of four permeation enhancers—sodium dodecyl sulfate, chitosan, ethylenediaminetetraacetic acid (EDTA), and caprate—on drug permeability and transport of chromium EDTA (an established clinical marker for intestinal barrier integrity) was determined. There was no difference in jejunal and colonic permeability determined from plasma appearance data of any of the four model drugs. This questions the validity of the rat single-pass intestinal perfusion model for predicting human regional intestinal permeability. It was also shown that the effect of permeation enhancers on drug permeability in the colon was similar to previously reported data from the rat jejunum, whereas the transport of chromium EDTA was significantly higher (p < 0.05) in the colon than in jejunum. Therefore, the use of permeation enhancers for increasing colonic drug permeability has greater risks than potential medical rewards, as indicated by the higher permeation of chromium EDTA compared to the drugs. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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13 pages, 4133 KiB

Open AccessArticle

Enteric Hard Capsules for Targeting the Small Intestine: Positive Correlation between In Vitro Disintegration and Dissolution Times

by Maoqi Fu, Jozef Al-Gousous, Johannes Andreas Blechar and Peter Langguth

Pharmaceutics 2020, 12(2), 123; https://doi.org/10.3390/pharmaceutics12020123 - 03 Feb 2020

Cited by 11 | Viewed by 3731

Abstract

In this study, the potential for correlation between disintegration and dissolution performance of enteric-coated (EC) dosage forms was investigated. Different enteric hard shell capsule formulations containing caffeine as model drug were tested for disintegration (in a compendial disintegration tester) and for dissolution in [...] Read more.

In this study, the potential for correlation between disintegration and dissolution performance of enteric-coated (EC) dosage forms was investigated. Different enteric hard shell capsule formulations containing caffeine as model drug were tested for disintegration (in a compendial disintegration tester) and for dissolution in both USP type I (basket) and type II (paddle) apparatuses using different media. Overall, good correlations were obtained. This was observed for both the basket and the paddle apparatus, indicating that the use of disintegration testing as a surrogate for dissolution testing (allowed by International Conference on Harmonization (ICH) for immediate release dosage forms in case, in addition to other conditions, a correlation between disintegration and dissolution is proven) could be extended to include delayed release dosage forms. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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28 pages, 5217 KiB

Open AccessArticle

A Mechanistic Physiologically-Based Biopharmaceutics Modeling (PBBM) Approach to Assess the In Vivo Performance of an Orally Administered Drug Product: From IVIVC to IVIVP

by Marival Bermejo, Bart Hens, Joseph Dickens, Deanna Mudie, Paulo Paixão, Yasuhiro Tsume, Kerby Shedden and Gordon L. Amidon

Pharmaceutics 2020, 12(1), 74; https://doi.org/10.3390/pharmaceutics12010074 - 17 Jan 2020

Cited by 40 | Viewed by 11275

Abstract

The application of in silico modeling to predict the in vivo outcome of an oral drug product is gaining a lot of interest. Fully relying on these models as a surrogate tool requires continuous optimization and validation. To do so, intraluminal and systemic [...] Read more.

The application of in silico modeling to predict the in vivo outcome of an oral drug product is gaining a lot of interest. Fully relying on these models as a surrogate tool requires continuous optimization and validation. To do so, intraluminal and systemic data are desirable to judge the predicted outcomes. The aim of this study was to predict the systemic concentrations of ibuprofen after oral administration of an 800 mg immediate-release (IR) tablet to healthy subjects in fasted-state conditions. A mechanistic oral absorption model coupled with a two-compartmental pharmacokinetic (PK) model was built in Phoenix WinNonlinWinNonlin^® software and in the GastroPlus™ simulator. It should be noted that all simulations were performed in an ideal framework as we were in possession of a plethora of in vivo data (e.g., motility, pH, luminal and systemic concentrations) in order to evaluate and optimize these models. All this work refers to the fact that important, yet crucial, gastrointestinal (GI) variables should be integrated into biopredictive dissolution testing (low buffer capacity media, considering phosphate versus bicarbonate buffer, hydrodynamics) to account for a valuable input for physiologically-based pharmacokinetic (PBPK) platform programs. While simulations can be performed and mechanistic insights can be gained from such simulations from current software, we need to move from correlations to predictions (IVIVC → IVIVP) and, moreover, we need to further determine the dynamics of the GI variables controlling the dosage form transit, disintegration, dissolution, absorption and metabolism along the human GI tract. Establishing the link between biopredictive in vitro dissolution testing and mechanistic oral absorption modeling (i.e., physiologically-based biopharmaceutics modeling (PBBM)) creates an opportunity to potentially request biowaivers in the near future for orally administered drug products, regardless of its classification according to the Biopharmaceutics Classification System (BCS). Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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10 pages, 2026 KiB

Open AccessArticle

Investigation to Explain Bioequivalence Failure in Pravastatin Immediate-Release Products

by Alejandro Ruiz-Picazo, Sarin Colón-Useche, Blanca Perez-Amorós, Marta González-Álvarez, Irene Molina-Martínez, Isabel González-Álvarez, Alfredo García-Arieta and Marival Bermejo

Pharmaceutics 2019, 11(12), 663; https://doi.org/10.3390/pharmaceutics11120663 - 09 Dec 2019

Cited by 9 | Viewed by 3410

Abstract

The purpose of this work is to explore the predictive ability of the biopharmaceutics classification system (BCS) biowaiver based on the dissolution methods for two pravastatin test products, where one of them showed bioequivalence (BE) while the other test failed (non-bioequivalence, or NBE), [...] Read more.

The purpose of this work is to explore the predictive ability of the biopharmaceutics classification system (BCS) biowaiver based on the dissolution methods for two pravastatin test products, where one of them showed bioequivalence (BE) while the other test failed (non-bioequivalence, or NBE), and to explore the reasons for the BE failure. Experimental solubility and permeability data confirmed that pravastatin is a BCS class III compound. The permeability experiments confirmed that the NBE formulation significantly increased pravastatin permeability, and could explain its higher absorption rate and higher C_max. This finding highlights the relevance of requiring similar excipients for BCS class III drugs. The BCS-based biowaiver dissolution tests at pH 1.2, 4.5, and 6.8, with the paddle apparatus at 50 rpm in 900 mL media, were not able to detect differences in pravastatin products, although the NBE formulation exhibited a more rapid dissolution at earlier sampling times. Dissolution tests conducted in 500 mL did not achieve complete dissolution, and both formulations were dissimilar because the amount dissolved at 15 min was less than 85%. The difference was less than 10% at pH 1.2 and 4.5, while at pH 6.8 f₂, results reflected the C_max rank order. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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Review

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23 pages, 1868 KiB

Open AccessReview

Enteroendocrine Hormone Secretion and Metabolic Control: Importance of the Region of the Gut Stimulation

by Cong Xie, Karen L. Jones, Christopher K. Rayner and Tongzhi Wu

Pharmaceutics 2020, 12(9), 790; https://doi.org/10.3390/pharmaceutics12090790 - 21 Aug 2020

Cited by 24 | Viewed by 5043

Abstract

It is now widely appreciated that gastrointestinal function is central to the regulation of metabolic homeostasis. Following meal ingestion, the delivery of nutrients from the stomach into the small intestine (i.e., gastric emptying) is tightly controlled to optimise their subsequent digestion and absorption. [...] Read more.

It is now widely appreciated that gastrointestinal function is central to the regulation of metabolic homeostasis. Following meal ingestion, the delivery of nutrients from the stomach into the small intestine (i.e., gastric emptying) is tightly controlled to optimise their subsequent digestion and absorption. The complex interaction of intraluminal nutrients (and other bioactive compounds, such as bile acids) with the small and large intestine induces the release of an array of gastrointestinal hormones from specialised enteroendocrine cells (EECs) distributed in various regions of the gut, which in turn to regulate gastric emptying, appetite and postprandial glucose metabolism. Stimulation of gastrointestinal hormone secretion, therefore, represents a promising strategy for the management of metabolic disorders, particularly obesity and type 2 diabetes mellitus (T2DM). That EECs are distributed distinctively between the proximal and distal gut suggests that the region of the gut exposed to intraluminal stimuli is of major relevance to the secretion profile of gastrointestinal hormones and associated metabolic responses. This review discusses the process of intestinal digestion and absorption and their impacts on the release of gastrointestinal hormones and the regulation of postprandial metabolism, with an emphasis on the differences between the proximal and distal gut, and implications for the management of obesity and T2DM. Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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23 pages, 3385 KiB

Open AccessReview

The Segregated Intestinal Flow Model (SFM) for Drug Absorption and Drug Metabolism: Implications on Intestinal and Liver Metabolism and Drug–Drug Interactions

by K. Sandy Pang, H. Benson Peng and Keumhan Noh

Pharmaceutics 2020, 12(4), 312; https://doi.org/10.3390/pharmaceutics12040312 - 01 Apr 2020

Cited by 9 | Viewed by 5025

Abstract

The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the [...] Read more.

The properties of the segregated flow model (SFM), which considers split intestinal flow patterns perfusing an active enterocyte region that houses enzymes and transporters (<20% of the total intestinal blood flow) and an inactive serosal region (>80%), were compared to those of the traditional model (TM), wherein 100% of the flow perfuses the non-segregated intestine tissue. The appropriateness of the SFM model is important in terms of drug absorption and intestinal and liver drug metabolism. Model behaviors were examined with respect to intestinally (M1) versus hepatically (M2) formed metabolites and the availabilities in the intestine (F_I) and liver (F_H) and the route of drug administration. The %contribution of the intestine to total first-pass metabolism bears a reciprocal relation to that for the liver, since the intestine, a gateway tissue, regulates the flow of substrate to the liver. The SFM predicts the highest and lowest M1 formed with oral (po) and intravenous (iv) dosing, respectively, whereas the extent of M1 formation is similar for the drug administered po or iv according to the TM, and these values sit intermediate those of the SFM. The SFM is significant, as this drug metabolism model explains route-dependent intestinal metabolism, describing a higher extent of intestinal metabolism with po versus the much reduced or absence of intestinal metabolism with iv dosing. A similar pattern exists for drug–drug interactions (DDIs). The inhibitor or inducer exerts its greatest effect on victim drugs when both inhibitor/inducer and drug are given po. With po dosing, more drug or inhibitor/inducer is brought into the intestine for DDIs. The bypass of flow and drug to the enterocyte region of the intestine after intravenous administration adds complications to in vitro–in vivo extrapolations (IVIVE). Full article

(This article belongs to the Special Issue Regional Intestinal Drug Absorption: Biopharmaceutics and Drug Formulation)

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