Evaluation of in vivo dissolution behavior and GI transit of griseofulvin, a BCS class II drug

Mean plasma concentration-time profile of griseofulvin, a BCS class II drug, orally administered as powders into rats, was predicted based on GITA model. However, it was very difficult to predict the individual plasma profile because of large inter-individual difference. As the absorption of griseofulvin would be rate-limited by the dissolution process, we tried to analyze the in vivo dissolution kinetics of griseofulvin by focusing on gastric emptying and intestinal transit as physiological factors influencing the in vivo dissolution kinetics. After oral administration of griseofulvin, theophylline and sulfasalazine into rats, gastric emptying and intestinal transit were simultaneously estimated by analyzing the absorption kinetics of theophylline and observing the appearance of sulfapyridine in plasma, respectively. Gastric emptying kinetics was not significantly correlated with absorption or dissolution behavior of griseofulvin. On the other hand, the cecum-arriving time reflecting the intestinal transit was significantly correlated with both AUC and total dissolved amount of griseofulvin. T(max) of griseofulvin also increased with the increase of cecum-arriving time. These results clearly indicate that the longer residence time could lead to the higher dissolution and absorption of griseofulvin and that the variance of intestinal transit could be responsible for the inter-individual difference of the in vivo absorption behavior.     

Gastrointestinal transit and drug absorption

The gastrointestinal (GI) absorption of orally administered drugs is determined by not only the permeability of GI mucosa but also the transit rate in the GI tract. It is well known that the gastric emptying rate is an important factor affecting the plasma concentration profile of orally administered drugs, and the intestinal transit rate also has a significant influence on the drug absorption, since it determines the residence time of the drug in the absorption site. The reason why the residence time is also a critical factor for drug absorption is that there is the site difference in absorbability for some drugs. We have developed the GI-Transit-Absorption Model (GITA Model) to analyze and predict the drug absorption kinetics by taking into account both the two factors, ie. GI transit and drug absorbability including its site difference. GITA Model has been already evidenced to be very useful for estimating the absorption kinetics of drugs with various characteristics and applied to assess the human data in combination with the gamma scintigraphy. In this review, the importance of GI transit rate in determining the absorption kinetics and the bioavailability of orally administered drugs is discussed mainly employing GITA Model and the results obtained by the model.     

Evaluation of absorption kinetics of orally administered theophylline in rats based on gastrointestinal transit monitoring by gamma scintigraphy

The gastrointestinal (GI) transit and absorption of orally administered theophylline, a highly absorbable drug without presystemic elimination, were investigated under fasted and fed conditions using three rats in a crossover study. To evaluate the GI transit rate for each segment in vivo, a noninvasive technique, gamma scintigraphy, was employed using a nonabsorbable compound, (99m)Tc-labeled diethylenetriamine pentaacetic acid (DTPA). Using a gamma scintigraphic technique it is possible to simultaneously evaluate the GI transit and absorption of orally administered drug in the same individual. Theophylline was simultaneously administered along with [(99m)Tc]DTPA to animals in the fasted and fed states. Each GI transit pattern, simulated using the GI transit-kinetic model with a lag time factor, was well fitted to the experimental data. Gastric emptying rate varied in each study, even under the same experimental condition. The GI transit pattern for each segment was highly variable, especially in animals in the fed state. This inconsistency in transit pattern was mainly due to the variability in gastric emptying, which was much slower in animals in the fed compared with the fasted state. However, in spite of a large variability of GI transit kinetics, the plasma concentration-time curves of theophylline were well predicted by the GI transit-absorption model using the individual GI transit parameters obtained in the study. The absorption rate of theophylline was considerably reduced in animals in the fed state, because of the reduction of gastric emptying rate. Analysis using GI transit-absorption model and gamma scintigraphic technique made it possible to estimate the variable absorption kinetics regulated by GI transit with huge variability.     

Prediction of plasma concentration-time curve of orally administered theophylline based on a scintigraphic monitoring of gastrointestinal transit in human volunteers

The plasma concentration-time profile of theophylline after oral administration in human volunteers was predicted using the individual gastrointestinal (GI) transit data monitored by a gamma scintigraphic technique. Theophylline was administered as aminophylline under fasted and fed condition, along with 99mTc-labeled diethylenetriamine-pentaacetic acid (DTPA), an unabsorbable marker to evaluate the GI transit by a gamma scintigraphic technique. Two healthy male volunteers participated under fasted and fed conditions in a crossover study. The GI transit was evaluated by dividing the GI tract to four segments, stomach, jejunum, ileum and cecum/colon. Under the fed condition, the GI transit pattern for each segment was confirmed to alter considerably, causing a delay in the gastric emptying mainly. Further, the plasma concentration curves of theophylline after oral administration were predicted using the GI-Transit-Absorption Model on the basis of individual GI transit parameters calculated by the fitting of the observed data to the GI-Transit Kinetic Model. The absorption rate constant in each segment and the pharmacokinetic parameters after intravenous administration used for the prediction were the values extrapolated from the data in rats and the ones normalized from the values in literatures, respectively. The plasma concentration-time curves for theophylline were well predicted using obtained individual GI transit parameters. The analysis using this method could estimate the variable absorption behavior governed by the GI transit in detail.     

Prediction of the Plasma Concentration Profiles of Orally Administered Drugs in Rats on the Basis of Gastrointestinal Transit Kinetics and Absorbability

A new method based on gastrointestinal transit kinetics has been developed for estimation of the absorption profiles of drugs administered orally as aqueous solutions. The utility of the method was evaluated in rats. The gastrointestinal transit profile for each segment was estimated by in-vivo studies using phenol red, an unabsorbable marker. The gastrointestinal transit profile of phenol red was well explained by a linear gastrointestinal transit kinetic model with eight segments. We also introduced the absorption process into the gastrointestinal transit kinetic model and the plasma profile was predicted by the convolution method. The absorbability of drugs in each segment was assessed by an in-situ absorption study. The validity of the model was evaluated for model drugs with different absorption characteristics. The plasma profiles predicted for ampicillin, theophylline and cephalexin were in good agreement with those observed. The overestimated plasma profile of propranolol suggests that the low bioavailability of propranolol is a result of first-pass metabolism by the intestine wall and the liver, because the calculated absolute absorption is almost perfect. This proposed model is also suitable for estimation of segmental absorption, which is useful for the development of drug delivery systems. We have demonstrated that the plasma profile of orally administered drugs can be predicted by use of gastrointestinal transit and segmental absorbability information and that this method is especially useful for estimating separately the effect of absolute absorption and first-pass metabolism on the bioavailability of drugs.     

Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time

Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of non-absorbable phenol red. The measured local GI concentration of phenol red ranged from 0.05 to 168 μg/mL (stomach), to 563 μg/mL (duodenum), to 202 μg/mL (proximal jejunum), and to 478 μg/mL (distal jejunum). The DFCAT model characterized observed MRI fluid volume and its dynamic changes from 275 to 46.5 mL in stomach (from 0 to 30 min) with mucus layer volume of 40 mL. The volumes of the 30 small intestine compartments were characterized by a max of 14.98 mL to a min of 0.26 mL (0–120 min) and a mucus layer volume of 5 mL per compartment. Regional fluid volumes over 0 to 120 min ranged from 5.6 to 20.38 mL in the proximal small intestine, 36.4 to 44.08 mL in distal small intestine, and from 42 to 64.46 mL in total small intestine. The DFCAT model can be applied to predict drug dissolution and absorption in the human GI tract with future improvements.     

Analysis and prediction of absorption profile including hepatic first-pass metabolism of N-methyltyramine, a potent stimulant of gastrin release present in beer, after oral ingestion in rats by gastrointestinal-transit-absorption model.

The prediction method for the plasma concentration-time profile of N-methyltyramine (NMT), a potent stimulant of gastrin release present in beer after oral ingestion in rats was examined using the previously developed Gastrointestinal (GI)-Transit-Absorption Model, with the addition of a process of hepatic first-pass metabolism. Phenol red was used as a nonabsorbable marker for estimation of the GI transit rate constant for eight segments in the GI tract. The first order absorption rate constant for each segment was estimated by means of a conventional in situ closed loop method. The results of in situ absorption experiments showed that NMT is well absorbed in the small intestine, especially in the duodenum and jejunum. Using the GI-Transit-Absorption Model, it was demonstrated that more than 90% of orally ingested NMT is absorbed in the small intestine, and that the substantial absorption site for NMT in vivo is the lower jejunum and the ileum. However, the observed bioavailability was only 39.0%. The in vitro metabolism study clarified that NMT is metabolized in the liver, but not in the small-intestinal mucosa. With the hepatic intrinsic clearance value (2.0 liters/h) calculated from the rate of metabolism in vitro, the hepatic availability was estimated to be 0.510 on the basis of a well stirred model, which was validated by two other methods to calculate the hepatic availability of NMT. The plasma concentration-time curve and bioavailability of NMT after oral ingestion were well predicted by the GI-Transit-Absorption Model with the hepatic first-pass metabolism process.     

Whole‐body physiologically based pharmacokinetic population modelling of oral drug administration: inter‐individual variability of cimetidine absorption

Objectives Inter‐individual variability of gastrointestinal physiology and transit properties can greatly influence the pharmacokinetics of an orally administered drug in vivo. To predict the expected range of pharmacokinetic plasma concentrations after oral drug administration, a physiologically based pharmacokinetic population model for gastrointestinal transit and absorption was developed and evaluated. Methods Mean values and variability measures of model parameters affecting the rate and extent of cimetidine absorption, such as gastric emptying, intestinal transit times and effective surface area of the small intestine, were obtained from the literature. Various scenarios incorporating different extents of inter‐individual physiological variability were simulated and the simulation results were compared with experimental human study data obtained after oral cimetidine administration of four different tablets with varying release kinetics. Key findings The inter‐individual variability in effective surface area was the largest contributor to absorption variability. Based on in‐vitro dissolution profiles, the mean plasma cimetidine concentration–time profiles as well as the inter‐individual variability could be well described for three cimetidine formulations. In the case of the formulation with the slowest dissolution kinetic, model predictions on the basis of the in‐vitro dissolution profile underestimated the plasma exposure. Conclusions The model facilitates predictions of the inter‐individual pharmacokinetic variability after oral drug administration for immediate and extended‐release formulations of cimetidine, given reasonable in‐vitro dissolution kinetics.     

A distribution study with (14)C-otilonium bromide in the rat: evidence for selective tropism for large intestine after oral administration.

The aim of this study was to determine the plasma levels and the tissue distribution of otilonium bromide, measured as total radioactivity, after oral administration of 2 mg/kg of (14)C-labeled drug to rats. Radioactivity levels were very low in the plasma (ranging from 2.7 ng Eq/ml at 1.5 h to 0.6 ng Eq/ml at 24 h) as compared with those found in the gastrointestinal (GI) tract, indicating negligible systemic otilonium bromide absorption. Results from both quantitative radioluminography of whole body tissue distribution and radioassay of dissected parts of the GI tract carried out with liquid scintillation counting clearly demonstrate the presence of radioactive compounds in the walls of the GI tract at all sacrifice times. In the other tissues and organs examined, radioactivity was only found in trace amounts in the liver. The presence of radioactivity in the GI walls reflected the transit kinetics of drug-enriched contents. The radioactivity in large intestine walls was measurable at otilonium bromide concentrations in the range of micromole equivalents/kg, from 4 to 8 h after drug administration. Total body radioactivity recovery was 95, 101, 24, and 9% at 1.5, 4, 8, and 24 h, respectively. In conclusion, orally administered (14)C-otilonium bromide is poorly absorbed systemically, as indicated by the very low plasma radioactivity levels, but it is able to effectively penetrate into the large intestine walls, a recognized target for drugs oriented toward irritable bowel syndrome therapy.     

Effect of pH on the in vitro dissolution and in vivo absorption of controlled-release theophylline in dogs

Dogs were used to examine the effect of elevated gastric pH on the absorption of controlled-released theophylline dosage forms with pH-dependent dissolution. In vitro studies showed that a controlled-release theophylline tablet dissolved more rapidly if it was initially exposed to an acidic media. In contrast, a controlled-release theophylline beaded capsule was slightly more rapidly dissolved in the absence of an initial exposure to an acidic media. Gastric pH was increased from 0.5-2.5 to 4.5-7.0 in four dogs by using 150-mg ranitidine HCl tablets, administered every 3 h, to induce an achlorhydric condition. Gastric pH was monitored using a Heidelberg capsule. Ranitidine was shown to have no apparent effect on the absorption or clearance of theophylline administered to the dogs as an oral liquid. The mean area under the concentration-time curve to infinity (AUCinf) for the controlled-release theophylline tablet was 21% greater (p less than 0.05) when administered to the four dogs without ranitidine treatment, compared with that following dosing with ranitidine. In contrast, the controlled-release beaded capsule exhibited a 10% greater AUCinf when ranitidine was given concomitantly. In general, ranitidine-induced changes in the in vivo absorption rate parameters for both dosage forms were opposite to those predicted from the in vitro dissolution rates. The results of this study demonstrated that the extent of theophylline absorption from controlled-release dosage forms, in control dogs and dogs with ranitidine-induced achlorhydria, corresponds to the pH-dependent in vitro dissolution properties of the products.     

Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract.

This study was conducted to assess the site of drug absorption in the gastrointestinal (GI) tract after oral administration. Drug permeability to different regions of rat intestine, jejunum, ileum and colon, was measured by in situ single-pass perfusion method. It was revealed that the epithelial surface area should not be a determinant of the regional difference in the intestinal permeability of highly permeable drugs. Effects of the mucus layer at the surface of the epithelium and the fluidity of the epithelial cell membrane on the drug permeability were investigated. These factors are demonstrated to contribute to the regional differences in intestinal drug permeability. The luminal drug concentration in each segment of the GI tract after oral administration was measured directly in fasted rats. Water ingested orally was absorbed quickly in the jejunum and the luminal fluid volume was diminished in the middle to lower part of the small intestine. According to the absorption of water luminal concentration of atenolol, a drug with low permeability, was elevated and exceeded the initial dose concentration. In contrast, the concentration of highly permeable drugs, antipyrine and metoprolol, decreased quickly in the upper part of the intestine and a significant amount of drugs was not detected in the lower jejunum and the ileum. From the time-profiles of luminal drug concentration, fraction of dose absorbed from each segment of the GI tract was calculated. Both antipyrine and metoprolol were found to be absorbed quickly at the upper part of the small intestine. In addition, the possible contribution of gastric absorption was demonstrated for these drugs. The pattern of site-dependent absorption of atenolol showed the higher absorbability in the middle and lower portion of the jejunum. These informations on site-dependent absorption of drugs are considered to be important for effective oral delivery systems.     

Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part II: extension to describe performance of solid dosage forms

The physiological absorption model presented in part I of this work is now extended to account for dosage-form-dependent gastrointestinal (GI) transit as well as disintegration and dissolution processes of various immediate-release and modified-release dosage forms. Empirical functions of the Weibull type were fitted to experimental in vitro dissolution profiles of solid dosage forms for eight test compounds (aciclovir, caffeine, cimetidine, diclofenac, furosemide, paracetamol, phenobarbital, and theophylline). The Weibull functions were then implemented into the model to predict mean plasma concentration-time profiles of the various dosage forms. On the basis of these dissolution functions, pharmacokinetics (PK) of six model drugs was predicted well. In the case of diclofenac, deviations between predicted and observed plasma concentrations were attributable to the large variability in gastric emptying time of the enteric-coated tablets. Likewise, oral PK of furosemide was found to be predominantly governed by the gastric emptying patterns. It is concluded that the revised model for GI transit and absorption was successfully integrated with dissolution functions of the Weibull type, enabling prediction of in vivo PK profiles from in vitro dissolution data. It facilitates a comparative analysis of the parameters contributing to oral drug absorption and is thus a powerful tool for formulation design.     

A Physiologic Model for Simulating Gastrointestinal Flow and Drug Absorption in Rats

PURPOSE: The development of a physiologically based absorption model for orally administered drugs in rats is described. METHODS: Unlike other models that use a multicompartmental approach, the GI tract is modeled as a continuous tube with spatially varying properties. The mass transport through the intestinal lumen is described via an intestinal transit function. The only substance-specific input parameters of the model are the intestinal permeability coefficient and the solubility in the intestinal fluid. With this physiologic and physicochemical information, the complete temporal and spatial absorption profile can be calculated. RESULTS: A first performance test using portal concentration data published in the literature yielded an excellent agreement between measured and simulated temporal absorption profiles in the portal vein. Furthermore, the dose dependence of a compound with solubility-limited fraction dose absorbed in rats (chlorothiazide) could be adequately described by the model. CONCLUSIONS: The continuous absorption model is well suited to simulate drug flow and absorption in the GI tract of rats.     

Pharmacokinetics of 7-carboxymethyloxy-3',4',5-trimethoxy flavone (DA-6034), a derivative of flavonoid, in mouse and rat models of chemically-induced inflammatory bowel disease

The pharmacokinetics (including distribution in the gastrointestinal tract) of 7-carboxymethyloxy-3',4',5-trimethoxy flavone (DA-6034) has been investigated in several mouse and rat models of chemically-induced inflammatory bowel disease (IBD). In the female ICR mouse model, IBD was induced by dextran sulfate and the mice administered 30 mg kg(-1) DA-6034 intravenously or orally. In the male SJL mouse model of IBD induced by oxazolone, 30 mg kg(-1) DA-6034 was administered orally. In the male Sprague-Dawley rat model of IBD induced by trinitrobenzene sulfonic acid (TNBS), 10 mg kg(-1) DA-6034 was administered intravenously and orally. After intravenous administration, the total area under the plasma concentration-time curve from time zero to the last measured time, t, in plasma (AUC(0-t)) values were comparable between control and dextran sulfate-induced IBD mice, and between control and TNBS-induced rats. This suggested that the disposition of DA-6034 was not affected considerably by dextran sulfate in mice and TNBS in rats. However, after oral administration in mice and rats with IBD, the AUC(0-t) values were greater compared with the respective controls. This could have been due to an increase (slow) in the gastrointestinal transit time (in IBD mice and rats, the percentages of the oral dose recovered from the rinsing fluid of the small intestine and large intestine as unchanged drug were greater and smaller, respectively), and an increase in intestinal permeability.     

A novel apparatus for rat in vivo evaluation of dry powder formulations for pulmonary administration

The lungs have attracted increasing attention as a site for administration of drugs, including macromolecules that are poorly absorbed from the intestine. There have been a number of basic studies in which peptide solutions were administered to experimental animals via the lungs. Although there have been several studies of pulmonary peptide absorption from dry powder formulations, a simpler and more inexpensive apparatus for administration of dry powders would enhance rapid screening of the formulations. In this study, we developed a simple apparatus to disperse dry powders. The apparatus has two 3-way stopcocks; one allows dispersal of powders at a constant pressure and airflow, and the other allows rats to breathe before and after administration. Dry powders of fluorescein (FL) and FITC-dextran (FD4) were manufactured by the spray-drying technique. The effects of operating conditions on the absorption of these model drugs were examined in rats. The C(max) for FL from dry powder was lower than that from solution and mean residence time was extended, suggesting that dissolution was the rate-determining step for FL absorption from dry powder. For FD4, the rate of absorption may not be regulated by dissolution but by epithelial transport. Absorption of insulin from spray-dried powder via the rat trachea was investigated using this apparatus. Intratracheally administered spray-dried insulin powder decreased plasma glucose level to a greater extent than spray-dried insulin solution administered via the same route. Thus, the apparatus is simple, inexpensive, and useful for rapid screening of dry powder formulations.     

A profile of the rat gastrointestinal toxicity of drugs used to treat inflammatory diseases

The gastrointestinal (GI) toxicity of some immunologic agents (IA) and some nonsteroidal anti-inflammatory agents (NAA) was studied in two rat models. The first model was designed to detect the potential of drugs for producing gastric lesions. Drugs were administered orally to fasted rats and the stomachs were examined 0.5, 1, 2, 4, 8, 16, and 32 hr after dosing. The second model was designed to evaluate the toxic effects on the small intestine. Drugs were administered daily by the oral route for 4 days. Groups of rats were killed at 24-hr intervals and the stomach and small intestine were examined. The results show that the drugs evaluated can be divided into three categories. One category consists of IA, which cause only gastric mucosal bleeding. The second category consisting of acetaminophen, aspirin, and oxaprozin, causes gastric mucosal bleeding and gastric submucosal lesions. The third category, composed of NAA, causes gastric mucosal and submucosal lesions and perforations and/or adhesions of the small bowel.     

Biopharmaceutical studies on drug/conjugated-metabolite interactions. I. Fate of acetaminophen sulfate,a major conjugated metabolite of acetaminophen,in rats

The plasma elimination kinetics and intestinal absorption kinetics of acetaminophen sulfate (APAPS), a major conjugated metabolite of acetaminophen (APAP), indispensable for the kinetic elucidation of drug/APAPS interactions, were examined in rats. Plasma elimination kinetics of APAPS after i.v. administration could be described by a two-compartment model with linear parameters to the dose. The deconjugation of intravenously administered APAPS, i.e., the formation of APAP, was recognized in neither plasma, urine nor bile. Approx. 80% of intravenously administered APAPS was excreted as the unchanged form in the urine in 4 h while biliary excretion was only a few percent of the dose. Plasma profiles of APAPS after oral administration showed two peaks, but the second one disappeared when the rat was pretreated with kanamycin sulfate. However, APAPS permeation through the small- and the large-intestinal walls determined in situ was not altered after kanamycin treatment. High APAPS-hydrolyzing activities present in the cecal and colonic contents and the feces, but not in the small-intestinal contents, completely disappeared after kanamycin treatment. Thus, part of the orally administered APAPS was absorbed as the unchanged form from both the small and large intestines, and considerable amounts of the remainder were absorbed from the large intestine as APAP after enzymatic hydrolysis by the intestinal microflora during transit through the lower bowel.     

A site-specific controlled-release system for metformin

Oral absorption of the antihyperglycaemic agent metformin hydrochloride (MF-HCl) is confined to the upper part of the intestine, therefore rational controlled-release formulations of this drug should ensure a complete release during transit from stomach to jejunum. The aim of this study was the preparation of a system able to sustain release of high MF-HCl doses in compliance with the above requirement. Matrices (6 mm diameter; 50 mg weight) comprising varying drug-Precirol ATO 5 ratios were prepared by compression. The matrix containing 70% drug was coated on one face with Eudragit L100-55. Drug release to simulated gastric (SGF), jejunal (SJF) and ileal (SIF) fluids in sequence was studied using a modified USP rotating basket method. Release depended on drug load whereas it was independent of dissolution medium pH and hydrodynamics. Release kinetics were of radical t type and were determined by drug diffusion in aqueous pores created in the matrix by drug dissolution. An equation correlating rate-determining factors was developed, whereby the release pattern could be optimized. The half-coated matrix started release in SGF and completed it in SJF. The half-coated matrix, synchronizing drug release and matrix transit across the small intestine, may improve drug bioavailability and reduce side effects.     

Population <Emphasis Type="BoldItalic">In Vitro-In Vivo</Emphasis> Correlation Model Linking Gastrointestinal Transit Time,pH, and Pharmacokinetics: Itraconazole as a Model Drug

Purpose

To establish an in vitro-in vivo correlation (IVIVC) model for Sporanox and SUBA-itraconazole formulations and to understand the impact of gastrointestinal (GI) pH and transit times on itraconazole dissolution and absorption.

Methods

IVIVC was developed based on fed/fasted pharmacokinetic data from randomized cross-over trials, in vitro dissolution studies, and prior information about typical and between subject variability of GI pH and transit times. Data were analysed using the population modelling approach as implemented in NONMEM.

Results

Dissolution kinetics were described using first order models. The in vivo pharmacokinetics of itraconazole was described with a 2-compartment model with 4-transit absorption compartments. Pharmacokinetic profiles for fasted itraconazole periods were described based on the in vitro dissolution model, in vivo disposition model, and the prior information on GI pH and transit times. The IVIVC model indicated that drug dissolution in the fed state required an additional pH-independent dissolution pathway. The IVIVC models were presented in a ‘Shiny’ application.

Conclusion

An IVIVC model was established and internally evaluated for the two itraconazole formulations. The IVIVC model provides more insight into the observed variability of itraconazole pharmacokinetics and indicated that GI pH and transit times influence in vivo dissolution and exposure.

     

Food effects on gastrointestinal physiology and drug absorption

Food ingestion affects the oral absorption of many drugs in humans. In this review article, we summarize the physiological factors in the gastrointestinal (GI) tract that affect the in vivo performance of orally administered solid dosage forms in fasted and fed states in humans. In particular, we discuss the effects of food ingestion on fluid characteristics (pH, bile concentration, and volume) in the stomach and small intestine, GI transit of water and dosage forms, and microbiota. Additionally, case examples of food effects on GI physiology and subsequent changes in oral drug absorption are provided. Furthermore, the effects of food, especially fruit juices (e.g., grapefruit, orange, apple) and green tea, on transporter-mediated permeation and enzyme-catalyzed metabolism of drugs in intestinal epithelial cells are also summarized comprehensively.