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International audience; Background: Dual antiplatelet therapy constitutes the cornerstone of medical treatment in patients with ST elevation myocardial infarction (STEMI). However, oral antiplatelet agents, such as prasugrel or ticagrelor, are characterized by slow gastrointestinal drug absorption in the acute phase of STEMI, leading to decreased bioavailability and therefore delayed onset of platelet inhibition. Evidence suggests that administration of crushed tablets of the P2Y12 inhibitor prasugrel improves drug absorption and achieves earlier antiplatelet effects in STEMI patients undergoing primary percutaneous coronary intervention (PCI). However, the clinical implications of these pharmacokinetic and pharmacodynamic findings are unknown.Hypothesis: The present study is designed to test the hypothesis that patients presenting with STEMI planned for primary PCI will have improved markers of optimal reperfusion and clinical outcomes by prehospital administration of crushed tablets of prasugrel loading dose.Study design: COMPARE CRUSH (NCT03296540) is a randomized trial in a regionally organized ambulance care setting evaluating the efficacy and safety of pre-hospital loading dose with prasugrel crushed tablets versus integral tablets in approximately 674 patients presenting with STEMI planned for primary PCI. The independent primary endpoints are percentage of patients reaching thrombolysis in myocardial infarction (TIMI) flow grade 3 in the infarct-related artery at initial angiography, or achieving ≥70% ST-segment elevation resolution at 1 hour post-PCI. Secondary clinical endpoints are death, myocardial infarction, revascularization, and stent thrombosis followed up to 1 year. Moreover, the primary safety endpoint is bleeding events assessed at 48 hours.Conclusions: The COMPARE CRUSH trial will assess whether prehospital administration of loading dose prasugrel in form of crushed tablets - which is expected to provide faster platelet inhibition compared to standard treatment with integral tablets - results in improved reperfusion and clinical outcomes.

During the past two decades, small-molecule kinase inhibitors have proven to be valuable in the treatment of solid and haematological tumours. However, because of their oral administration, the intrapatient and interpatient exposure to small-molecule kinase inhibitors (SMKIs) is highly variable and is affected by many factors, such as concomitant use of food and herbs. Food–drug interactions are capable of altering the systemic bioavailability and pharmacokinetics of these drugs. The most important mechanisms underlying food–drug interactions are gastrointestinal drug absorption and hepatic metabolism through cytochrome P450 isoenzymes. As food–drug interactions can lead to therapy failure or severe toxicity, knowledge of these interactions is essential. This Review provides a comprehensive overview of published studies involving food–drug interactions and herb–drug interactions for all registered SMKIs up to Oct 1, 2019. We critically discuss US Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines concerning food-drug interactions and offer clear recommendations for their management in clinical practice.

The generation of reliable kinetic parameters to describe P-glycoprotein (P-gp) activity is essential for predicting the impact of efflux transport on gastrointestinal drug absorption. The compound-specific selection of in vitro assay designs and ensuing data analysis methods is explored in this manuscript. We measured transcellular permeability and cellular uptake of five P-gp substrates in Caco-2 and LLC-PK1 MDR1 cells. Kinetic parameters of P-gp-mediated efflux transport (Km, Vmax) were derived from conventional and mechanistic compartmental models. The estimated apparent Km values based on medium concentrations in the conventional permeability model indicated significant differences between the cell lines. The respective intrinsic Km values based on unbound intracellular concentrations in the mechanistic compartmental models were significantly lower and comparable between cell lines and assay formats. Non-specific binding or lysosomal trapping were shown to cause discrepancies in the kinetic parameters obtained from different assay formats. A guidance for the selection of in vitro assays and kinetic assessment methods is proposed in line with the Biopharmaceutics Drug Disposition Classification System (BDDCS). The recommendations are expected to aid the acquisition of robust and reproducible kinetic parameters of P-gp-mediated efflux transport.

The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlus™ to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo gastrointestinal aspiration study. Three different formulations were explored (i.e., 1 solution [20 mg dose strength] and 2 suspensions [both 40 mg dose strength]). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma Cmax). The optimization of the advanced compartmental and absorption transit model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging studies. ispartof: JOURNAL OF PHARMACEUTICAL SCIENCES vol:108 issue:1 pages:305-315 ispartof: location:United States status: published

The aim of this study was to explore the influence of food on P-glycoprotein (P-gp) relative expression in both male and female rats, and its effect on intestinal permeation of P-gp substrates (ranitidine and ganciclovir) and a P-gp non-substrate (metformin). The intestine of 12 male and 12 female Wistar rats were excised and segmented into the duodenum, jejunum, ileum and colon. P-gp extracted from each segment was then determined via Western-blotting. In male rats, the relative P-gp expression decreased significantly after food intake in all segments of the intestine except in the duodenum. The most notable change was demonstrated in the colon where relative expression decreased from 1.75 ± 0.36 in the fasted-state to 0.31 ± 0.15 in the fed-state. In female rats, a fundamentally different result was observed. Food ingestion resulted in a significant increase in relative P-gp expression in all regions of the intestine except in the colon. The largest difference was observed in the jejunum of the fed-state female rat intestine where P-gp expression was 1.76 ± 0.95 which was a six-fold increase from the fasted state at 0.34 ± 0.13. Intestinal permeation studies in an Ussing chamber showed that both ganciclovir and ranitidine exhibited a sex difference in intestinal permeability in the fasted-state. No sex differences and food effects were observed on metformin small intestine permeability. The permeability results of the three drugs highly supported that there was a sex-related food effect on P-gp function in the small intestine. In summary, the current study reports stark differences between male and female rats at a physiological level relating to P-gp expression and the influence of food.

Ensuring reliable gastrointestinal drug absorption of orally administered immunosuppressive medications posttransplant is critical to ensuring graft survival.A 66-year-old man of East Asian origin with a previous total gastrectomy was evaluated for living donor kidney transplantation. Pretransplant pharmacokinetic testing was performed to determine the most appropriate posttransplant medication strategy. The Gastrointestinal Quality of Life Index and Gastrointestinal Rating Scale questionnaires were administered to gauge immunosuppressive medication-related side effects in the absence of a stomach.The patient's ability to absorb cyclosporin, tacrolimus (Tac), enteric-coated mycophenolate sodium (EC-MPS) and sirolimus (SRL) in oral dosage forms was well-preserved. Compared to nongastrectomy reference populations, the rate and extent of absorption of SRL and mycophenolic acid from EC-MPS were similar. The absorption of Tac and cyclosporin was greater than expected. Mycophenolate mofetil did not provide mycophenolic acid absorption as well as EC-MPS. The patient had worsened gastrointestinal symptoms with mycophenolate mofetil or EC-MPS in combination with Tac and cyclosporin, but this was not seen with isolated SRL.This case demonstrates that commonly used postkidney transplantation immunosuppressive regimes may be prescribed after total gastrectomy as long as their limitations are noted.

OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development. ispartof: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS vol:152 pages:236-247 ispartof: location:Netherlands status: published

The small intestine is generally considered the major site of absorption after oral drug administration. Absorption from the stomach is often disregarded, though passive diffusion across the gastric mucosal barrier is theoretically possible. In this study, an in situ gastric bolus administration model was used to study the gastric absorption of pharmaceutical compounds in fasted and fed state rats. Three drugs [paracetamol (neutral), diclofenac (acidic) and posaconazole (basic)] were administered directly into the stomach as solution (paracetamol and diclofenac) or suspension (posaconazole). Transfer to the intestine was blocked by ligating the pylorus; as a reference, non-ligated conditions were used. Blood samples were collected and gastric absorption was assessed by the appearance of compounds in the systemic circulation. Paracetamol and diclofenac were readily absorbed from the fasted and fed state rat stomach. For paracetamol, the relative contribution of gastric absorption was higher in the fed state compared to the fasted state. Posaconazole absorption was negligible. Since the ability of the stomach to absorb pharmaceutical compounds was clearly confirmed, the present study warrants further research to quantify the contribution of gastric absorption to total gastrointestinal drug absorption.

The success of an oral drug route administration depends on many factors that interfere in its bioavailability, therapeutic efficacy and clinical safety. In human cells, ATP-dependent efflux transporter proteins, such as P-glycoprotein (P-gp), BCRP and MRP2, reduce the absorption of drugs. A tiered approach chosen to evaluate drugs as substrates or inhibitors of efflux pumps, particularly P-gp, should be carefully selected, since each study method has advantages and intrinsic limitations to their processes. Depending on the adopted study conditions, the results may not correspond to the real characteristics of the drug regarding to its modulation by specific efflux proteins. This mini-review aims at summarizing the role of P-gp in the drugs oral absorption and correlating some of the most used permeability methods to determine the drug condition as P-gp substrate. Studies about P-gp have shown that it is a dynamic protein, facilitating secretion of endogenous compounds, as aldosterone, and protecting cells against xenobiotics. Different efflux assays are employed to evaluate drugs as P-gp substrates. In an initial planning, MDCK-MDR1 tend to be the chosen method for efflux studies due its ability of express P-gp, followed by studies conducted in Caco-2 models. However, it is necessary to evaluate the advantages and disadvantages of each method to generate sound results and to set the correlation in vitro x in situ x in vivo.

This study aimed to construct a new local pharmacokinetic model of gastrointestinal absorption, the translocation model (TLM), using an anatomically relevant, minimally segmented structure to explain linear and nonlinear intestinal absorption, metabolism, and transport. The TLM was based on the concept of a single absorption site that flexibly moves, expands, and shrinks along with the length of the gastrointestinal tract after the intake of an oral dose. The structure of the small intestine is continuous, and various time- and location-dependent issues are freely incorporated in the analysis. Since the model has only one absorption site, understanding and modification of factors affecting absorption are simple. The absorption site is composed of four compartments: solid drug in the lumen, solution drug in the lumen, concentration in the enterocytes, and concentration in the lamina propria. The lamina propria includes the blood capillaries. Blood flow in the absorption site of the lamina propria appropriately accounts for the absorption. In the TLM, the permeability of the apical membrane and that of the basolateral membrane are distinct. By considering plicate, villi, and microvilli expansions of the surface area, the apparent permeability measured in Caco-2 experiments was converted to the effective permeability in vivo. The intestinal availability, bioavailability, and dose product of intestinal availability and absorption rate relationship of the model drugs were well explained using the TLM. The TLM would be a useful tool for the consideration of local pharmacokinetics in the gastrointestinal tract in various situations.

Women may benefit from hormone replacement therapy to alleviate undesirable menopausal symptoms such as hot flashes, disruption of sleep and fatigue. Transdermal hormone replacement therapy consists in the delivery of hormones through the skin and into the blood stream, avoiding gastrointestinal drug absorption difficulties and the first pass effect. Transdermal compounded medications may be customized to meet the individual needs of women by changing the hormones used, the respective concentrations and the medicine’s formulation. Two compounded medications were prepared for progesterone 50 mg/g, as follows: Progesterone in VersaBase® Cream and progesterone in VersaBase® Cream Gel. The purpose of this study is to determine the in vitro human skin percutaneous absorption of progesterone for both test formulations. The Franz Skin Finite Dose Model was the methodology used to evaluate the total absorption, the rate of absorption and the skin content of progesterone applied to the outer surface of ex vivo skin. This model has proven to be a valuable tool for the study of percutaneous absorption of topically applied drugs and to accurately predict in vivo permeation kinetics. The skin samples were obtained within 24 h to 48 h of death from three adult Caucasian donors and a total of 17 Franz diffusion chambers were prepared for testing. Results are presented as the mean ± standard error per parameter, for each test formulation. The rate of percutaneous absorption, presented as mean flux, was similar for the two test formulations and characterized by 2 peaks at approximately 6 hours and 28 hours after dose application, followed by a decline in flux over time. The total absorption and the skin content of progesterone were also similar: 21.6% and 21.8% of the applied doses for the test formulations 1 and 2, respectively. Although in vitro, these results suggest that progesterone in VersaBase® is likely to be delivered through the skin and into the general circulation for systemic effects. Practitioners may then consider transdermal progesterone as a viable route of drug administration for menopausal women.

Oral drug delivery is the predominant administration route for a major part of the pharmaceutical products used worldwide. Further understanding and improvement of gastrointestinal drug absorption predictions is currently a highly prioritized area of research within the pharmaceutical industry. The fraction absorbed (fabs) of an oral dose after administration of a solid dosage form is a key parameter in the estimation of the in vivo performance of an orally administrated drug formulation. This study discloses an evaluation of the predictive performance of the mechanistic physiologically based absorption model GI-Sim. GI-Sim deploys a compartmental gastrointestinal absorption and transit model as well as algorithms describing permeability, dissolution rate, salt effects, partitioning into micelles, particle and micelle drifting in the aqueous boundary layer, particle growth and amorphous or crystalline precipitation. Twelve APIs with reported or expected absorption limitations in humans, due to permeability, dissolution and/or solubility, were investigated. Predictions of the intestinal absorption for different doses and formulations were performed based on physicochemical and biopharmaceutical properties, such as solubility in buffer and simulated intestinal fluid, molecular weight, pK(a), diffusivity and molecule density, measured or estimated human effective permeability and particle size distribution. The performance of GI-Sim was evaluated by comparing predicted plasma concentration-time profiles along with oral pharmacokinetic parameters originating from clinical studies in healthy individuals. The capability of GI-Sim to correctly predict impact of dose and particle size as well as the in vivo performance of nanoformulations was also investigated. The overall predictive performance of GI-Sim was good as >95% of the predicted pharmacokinetic parameters (C(max) and AUC) were within a 2-fold deviation from the clinical observations and the predicted plasma AUC was within one standard deviation of the observed mean plasma AUC in 74% of the simulations. GI-Sim was also able to correctly capture the trends in dose- and particle size dependent absorption for the study drugs with solubility and dissolution limited absorption, respectively. In addition, GI-Sim was also shown to be able to predict the increase in absorption and plasma exposure achieved with nanoformulations. Based on the results, the performance of GI-Sim was shown to be suitable for early risk assessment as well as to guide decision making in pharmaceutical formulation development.

This is a reply to the comment on "In Silico Modeling of Gastrointestinal Drug Absorption: Predictive Performance of Three Physiologically Based Absorption Models" by Turner and other Simcyp associates. In the reply we address the major concerns raised by Turner et al. regarding the methodology to compare the predictive performance of the different absorption models and at the same time ensure that the systemic pharmacokinetic input was exactly the same for the different models; the selection of the human effective permeability value of fexofenadine; the adoption of model default values and settings; and how supersaturation/precipitation was handled. In addition, we also further discuss aspects related to differences in in silico models and the potential implications of such differences. Our original report should be viewed as the starting point in a thorough and transparent review of absorption prediction models with the overall aim of improving their application as validated tools for bridging studies of active pharmaceutical ingredients from various sources and origins in a regulatory context. With this reply we encourage other independent investigators to perform further model evaluations of commercial as well as other existing or recently implemented models. This will boost the overall progression of physiologically based biopharmaceutical models for predicting and simulating intestinal drug absorption both in research and development and in a regulatory context.

Gastrointestinal (GI) drug absorption is a complex process determined by formulation, physicochemical and biopharmaceutical factors, and GI physiology. Physiologically based in silico absorption models have emerged as a widely used and promising supplement to traditional in vitro assays and preclinical in vivo studies. However, there remains a lack of comparative studies between different models. The aim of this study was to explore the strengths and limitations of the in silico absorption models Simcyp 13.1, GastroPlus 8.0, and GI-Sim 4.1, with respect to their performance in predicting human intestinal drug absorption. This was achieved by adopting an a priori modeling approach and using well-defined input data for 12 drugs associated with incomplete GI absorption and related challenges in predicting the extent of absorption. This approach better mimics the real situation during formulation development where predictive in silico models would be beneficial. Plasma concentration-time profiles for 44 oral drug administrations were calculated by convolution of model-predicted absorption-time profiles and reported pharmacokinetic parameters. Model performance was evaluated by comparing the predicted plasma concentration-time profiles, Cmax, tmax, and exposure (AUC) with observations from clinical studies. The overall prediction accuracies for AUC, given as the absolute average fold error (AAFE) values, were 2.2, 1.6, and 1.3 for Simcyp, GastroPlus, and GI-Sim, respectively. The corresponding AAFE values for Cmax were 2.2, 1.6, and 1.3, respectively, and those for tmax were 1.7, 1.5, and 1.4, respectively. Simcyp was associated with underprediction of AUC and Cmax; the accuracy decreased with decreasing predicted fabs. A tendency for underprediction was also observed for GastroPlus, but there was no correlation with predicted fabs. There were no obvious trends for over- or underprediction for GI-Sim. The models performed similarly in capturing dependencies on dose and particle size. In conclusion, it was shown that all three software packages are useful to guide formulation development. However, as a consequence of the high fraction of inaccurate predictions (prediction error2-fold) and the clear trend toward decreased accuracy with decreased predicted fabs observed with Simcyp, the results indicate that GI-Sim and GastroPlus perform better than Simcyp in predicting the intestinal absorption of the incompletely absorbed drugs when a higher degree of accuracy is needed. In addition, this study suggests that modeling and simulation research groups should perform systematic model evaluations using their own input data to maximize confidence in model performance and output.

New strategies for tacrolimus administration that conserve its immunosuppressive effect but avoiding fluctuations in tacrolimus circulating levels are needed. The aim was to analyze if subcutaneous biodegradable tacrolimus-loaded microspheres injection promoted a significant immunosuppressive response in rats. Rats received two subcutaneous tacrolimus-loaded microspheres injections at different days, the first injection was done at day 0 and the second injection was done 12 days after. Plasma circulating levels of tacrolimus, interleukin-2 (IL-2) and calcineurin phosphatase (PP2B) activity in mononuclear cells were measured. Tacrolimus plasma levels were significantly increased from the day after tacrolimus-loaded microspheres injection and remained increased during 10days. Compared to control, plasma IL-2 levels and PP2B activity in mononuclear cells were significantly decreased during ten days. At day 12, a new subcutaneous injection of tacrolimus-loaded microspheres was performed and two days after injection, tacrolimus plasma levels were again increased and both IL-2 plasma levels and PP2B activity decreased. A single subcutaneous tacrolimus-loaded microspheres injection was enough to reduce tacrolimus-related immunosuppressive parameters. These results open the possibility of new therapeutic strategies to administrate calcineurin inhibitors reducing the variability of their circulating levels related to gastrointestinal drug absorption/metabolism modifications.

This study assessed the process of gastrointestinal drug absorption in vivo using PET. Methods:18F-FDG was used as a model probe and was orally administered to rats as a solution. PET scans were obtained of the whole body and abdominal region under conscious and anesthetized conditions. Blood samples were routinely taken from the femoral vein during scanning. The rate of gastric emptying and intestinal absorption of 18F-FDG was estimated from the time profiles of radioactivity in the stomach and small intestine. In addition, nonradiolabeled 2-fluoro-2-deoxy-d-glucose (2-FDG) was used in an intestinal closed-loop experiment to compare the intestinal permeability of 2-FDG with that of d-glucose. Results: In conscious rats, gastrointestinal absorption of 18F-FDG was rate-limited by the process of intestinal membrane permeation, because the permeability of 2-FDG through the intestinal membrane was low compared with that of d-glucose. In anesthetized rats, the gastric emptying rate of 18F-FDG decreased dramatically whereas the intestinal absorption rate constant was not significantly different from that in conscious rats. As a result, the rate-limiting step of gastrointestinal absorption of 18F-FDG was shifted to the gastric emptying process by anesthesia. Conclusion: PET technology is a powerful tool for in vivo analysis of the gastrointestinal absorption of orally administered drugs.

Many herbal medications are used to treat diseases but while they are often efficacious, their safety is rarely considered by physicians or users. One particular safety concern is the risk of interactions with drugs, which often lead to toxicity or loss of therapeutic efficacy. In order to assess this risk, it is important to consider all potential mechanisms of pharmacokinetic interference. A large number of in vivo and invitro experiments and clinical studies have cast light on the possible effects of botanical products and phytochemicals on the many enzymes and transporters involved in gastrointestinal drug absorption. This review gives an overview and assessment of the most widely sold herbal medicinal products, including liquorice, garlic, ginger, ginkgo, green tea, St. John's wort, saw palmetto, turmeric, valerian, milk thistle and echinacea, on the basis of the available scientific evidence. Sound knowledge of the mechanisms of herb-drug interactions is essential for clinical risk assessment, in turn vital to healthcare practitioners in their efforts to reduce minimise risk and ensure that taking herbal medicinal products is as safe as possible.

Possible factors of species differences in gastrointestinal drug absorption between cynomolgus monkeys and humans were examined using several commercial drugs. Oral bioavailability (BA) of acetaminophen, furosemide, and propranolol in cynomolgus monkeys was significantly lower than that in humans. From the pharmacokinetic analysis, these drugs were found to show the low fraction absorbed into portal vein (FaFg), suggesting that the low BA in cynomolgus monkeys was attributed mainly to the gastrointestinal absorption processes. The gastric emptying rate (GER) calculated from plasma concentration profiles after oral administration of acetaminophen in cynomolgus monkeys was similar in humans. The gastrointestinal transit time (GITT) in cynomolgus monkeys was only slightly shorter than that in humans. On the other hand, it was demonstrated that the apparent intestinal permeability (Papp) of five drugs to cynomolgus monkey intestine was lower than that to rat intestine; especially propranolol and furosemide showed the remarkably low Papp. The expression levels of mRNAs of efflux transporters analyzed by real-time RT-PCR indicated that mRNA expression levels of MDR1, MRP2, and BCRP in monkey intestine were significantly higher than those in human intestine. This result suggested that low oral absorption of furosemide in cynomolgus monkeys was attributed to the high activities of efflux transporters in its intestinal membrane. Results of in vivo PK analysis clearly showed that FaFg values of propranolol and acetaminophen in cynomolgus monkeys were markedly lower than those in humans. Since propranolol and acetaminophen were the drug with high membrane permeability, it was considered that the high first-pass metabolism in the enterocytes was a main factor of their low FaFg in cynomolgus monkeys. In conclusion, it was demonstrated that the high activities of efflux transporters and/or metabolizing enzymes in the intestinal membrane are possible factors to cause poor oral absorption of drugs in cynomolgus monkeys.

The majority (84%) of the 50 most-sold pharmaceutical products in the US and European markets are given orally. The dominating role of this route in drug therapy is a consequence of it being safe, efficient and easily accessible with minimal discomfort to the patient in comparison with other routes of drug administration. A successful drug discovery and development of oral pharmaceutical products require an in-depth understanding of multiple biochemical and physiological processes that determine the dissolution rate, intestinal permeability, gastrointestinal transit, first-pass extraction and systemic exposure-time profiles of drugs. It is crucial to realize that these basic biopharmaceutic and pharmacokinetic properties are crucial to focus on to allow successful drug development. Identification of the rate-limiting step(s) in order to overcome these barriers and understanding of the sources of variability are important in the selection of suitable candidate molecules in drug development. Several reports based on in vitro investigations in various cell models have suggested that carrier-mediated intestinal efflux may be a major reason for incomplete absorption and variable bioavailability of drugs, as well being a site for drug-drug and specific food-drug interactions. However, many drugs which were initially suggested to undergo significant efflux in vitro were later shown to be completely absorbed in vivo. This apparent discrepancy between in vitro and in vivo results may be due to several factors that will be discussed in this review. Novel data on solubility and dissolution in human gastrointestinal derived fluids will be reviewed. The effect of food intake on solubility and dissolution rate of a range of drugs including felodipine, danazol, griseofulvin, cyclosporine, probucol and ubiquinone in simulated and real intestinal fluids is discussed. The biopharmaceutic and physicochemical data discussed here can potentially be used as a benchmark set for validation of new experimental techniques or in silico models in future. Factors such as structural diversity, commercial availability, price and a suitable analytical technique for quantification were considered in the selection of a specific drug set. Using the compiled data set lipophilicity as determined by reverse phase HPLC and permeability across Caco-2 cell monolayers were determined; means to overcome the experimental difficulties due to the diversity of the data are also discussed.

The objective of this paper was to review existing information regarding food effects on drug absorption within paediatric populations. Mechanisms that underpin food–drug interactions were examined to consider potential differences between adult and paediatric populations, to provide insights into how this may alter the pharmacokinetic profile in a child. Relevant literature was searched to retrieve information on food–drug interaction studies undertaken on: (i) paediatric oral drug formulations; and (ii) within paediatric populations. The applicability of existing methodology to predict food effects in adult populations was evaluated with respect to paediatric populations where clinical data was available. Several differences in physiology, anatomy and the composition of food consumed within a paediatric population are likely to lead to food–drug interactions that cannot be predicted based on adult studies. Existing methods to predict food effects cannot be directly extrapolated to allow predictions within paediatric populations. Development of systematic methods and guidelines is needed to address the general lack of information on examining food–drug interactions within paediatric populations.

Advances in mathematics and physics that deal with fractal geometry, fractal kinetics and chaotic dynamics have offered new insights for complex, kinetic and dynamical phenomena. These concepts can be applied to describe the heterogeneous nature of drug processes in the human body. Using these concepts, all processes related to gastrointestinal drug absorption (i.e. dissolution or release, transit and uptake) are considered to take place in non-homogeneous, disordered media. In pharmacokinetic modeling, fractal spaces and branching transport networks, or stochastic models, replace the classical compartmental models. Classical pharmacodynamics relies on the suppression or amplification of a steady-state baseline; however, the underlying physiological systems are often much more complex. Therefore, tools of nonlinear dynamics are used to analyze the drug effect.

Organogenesis throughout childhood affects almost every aspect of pediatric pharmacotherapy. The antiepileptic drugs (AEDs) are particularly impacted since most elimination rates are diminished for the first 6 months of infancy, but quickly attain and supersede adult values. When children enter a hypermetabolic stage, large doses of AEDs may be necessary to maintain effective serum concentrations. Medication noncompliance is frequently confused as hypermetabolism, since both present with low serum drug concentrations. Amazingly, noncompliance among children with chronic illness approaches a similar incidence to that reported in the adult population. It is obviously important to include this in the differential diagnosis of the etiology of subtherapeutic serum AED concentrations. Maturational differences also affect gastrointestinal drug absorption. Intestinal transit time and absorptive surface area are both diminished in young children. Drug delivery systems suitable in adults may not deliver the total dosage in children. Differences in the composition of body compartments and protein binding can alter the volume of drug distribution and, consequently, serum concentrations. In addition to pathophysiologic changes, there is evidence to suggest differences between a mature and immature brain. These differences include quantitative and qualitative responses to neurotransmitters. Hence, it is understandable why seizure semiology is different in children compared with adults. This constellation of factors contributes to the challenges of caring for children with epilepsy.

The prevalence of nontuberculous mycobacteria (NTM) recovered from patients with cystic fibrosis (CF) appears to be increasing, probably related to improved surveillance and microbiological procedures and an increase in the life expectancy of patients with CF. The distinction between active lung infection and colonization is often difficult to assess in patients with CF because of the marked overlap in the clinical and radiological presentation of CF lung disease and lung disease caused by NTM infection. The possibility of active NTM lung infection should be considered in those patients with compatible radiographic changes and/or progressive deterioration in lung function who do not improve with specific antibiotic therapy and who have repeatedly positive sputum cultures and smears for NTM. Patients with repeatedly positive results of acid-fast smears are more likely to be infected than colonized. Pseudomonas overgrowth may confuse the results of sputum and bronchoalveolar lavage fluid cultures. Decontamination of respiratory samples from patients with CF with 5% oxalic acid results in improved bacteriological recovery of NTM. Skin tests are of limited value as a screening tool for NTM. Since the course of NTM lung infection is often slow, careful follow-up with repeated sputum cultures, chest radiographs and computed tomography (CT) scans may be needed. Treatment of NTM lung disease in patients with CF presents great difficulties because of abnormal gastrointestinal drug absorption and pharmacokinetics in this patient population. Treatment varies according to the mycobacterial species isolated. Long-term multidrug regimens including rifampin (rifampicin) and ethambutol are usually required. Monitoring serum drug levels is a useful indicator of correct dosage in order to prevent adverse effects due to potential drug interactions and altered pharmacokinetics in patients with CF.

The objectives of these studies were, first, to determine the effect of elevated luminal viscosity on the gastrointestinal absorption of four model drugs and, second, to identify the key processes influencing drug absorption under elevated viscosity conditions. Studies were conducted in vitro and in healthy female mongrel dogs under fasting conditions. In the canine model, both the rate and extent of paracetamol and hydrochlorothiazide absorption were significantly decreased by the coadministration of 15 g guar gum dissolved in 500 ml normal saline. In the case of cimetidine, the rate but not extent of absorption was decreased. Owing to the high variability in the data, no statistically based conclusion could be drawn about the effects of coadministered guar gum on the oral absorption of the poorly soluble mefenamic acid. Based on the in vitro data, it appears that substantial reductions in the dissolution rate of paracetamol, hydrochlorothiazide and cimetidine account for the effects observed in vivo. It is concluded that the effect of an elevation in the intraluminal viscosity on drug absorption is greatest for highly soluble drugs, and results from a combination of a decrease in dissolution rate and gastric emptying rate.

The current analysis of gastrointestinal absorption phenomena relies on the concept of homogeneity. However, drug dissolution, transit and uptake in the gastrointestinal tract are heterogeneous processes since they take place at interfaces of different phases under variable stirring conditions. Recent advances in physics and chemistry demonstrate that the geometry of the environment is of major importance for the treatment of heterogeneous processes. In this context, the heterogeneous character of in vivo drug dissolution, transit and uptake is discussed in terms of fractal concepts. Based on this analysis, drugs are classified in accordance with their gastrointestinal absorption characteristics into two broad categories i.e. homogeneous and heterogeneous. The former category includes drugs with satisfactory solubility and permeability which ensure the validity of the homogeneous hypothesis. Drugs with low solubility and permeability are termed heterogeneous since they traverse the entire gastrointestinal tract and therefore are more likely to exhibit heterogeneous dissolution, transit and uptake. The high variability of whole bowel transit and the unpredictability of conventional dissolution tests for heterogeneous drugs are interpreted on the basis of the fractal nature of these processes underin vivoconditions. The implications associated with the use of strict statistical criteria in bioequivalence studies for heterogeneous drugs are also pointed out.

The absorption enhancers improve drug absorption affecting both of transcellular and paracellular routes, and the effect of the enhancers is larger in the paracellular route opening the tight junction. Theses findings are based on the effects on depolarization of fluorescence in the brush border membrane, Solomon's equation, voltage clamp method and impedance analysis of the colonic membrane. The mechanism of tight junction opening by caprate (C10) that is one of representative enhancers is revealed that C10 releses Ca ion from the intracellular store and that the released Ca ion contracts the actin filament through the activation of myosin light chain kinase. But for other representative enhancers such EDTA and palmitoyl carnitine, other different mechanism is needed but not cleared yet. Glucose transporter is found to work for the glycoside absorption, and sugar coupling with some oligo peptides enhance the absorption not only by transporter use but also by stabilization of peptides. Vitamin A protects the damage of small intestine by methotrexate and improves the absorption of nutrients. Fluorescence spectra and protein aggregates which are produced during lipid peroxidation in the membrane such as microsome are measured directly from the membrane. They are used as indexes of the extent and site of lipid proxidation. The lipid peroxidation of heart mitochondria by doxorubicin (DXR) is demonstrated with these indexes. Chemiluminescence that is weak but measured very sensitively is also used as an index of lipid peroxidation. The chemiluminescence spectrum shows the production of the activated carbonyl and single oxygen during DXR oxidation. Naproxan which is known comparatively safe is revealed by the above indeces to give lipid peroxidation in liver during its metabolism. It is discussed that the lipid peroxidation in liver is a probable cause of liver damage which is occasionally reported for naproxen treatment.

During the 1950s, I was a student at the University of California School of Pharmacy in San Francisco. One of my favorite teachers was Dr. Eino Nelson, then a newly appointed assistant professor. I noticed that Eino spent a lot of time in the School’s balance room, in front of our only single pan analytical balance. I asked him about that and he told me that he was studying the intrinsic dissolution rate of a number of barbituric acid derivatives and their sodium salts. For this purpose, he prepared highly compressed flat pellets of pure drug and mounted them with wax on a microscope slide such that only one face of the pellet was exposed. The slide, suspended from the balance, was immersed in a beaker of water. The apparent weight loss of the immersed slide was then determined as a function of time, thereby providing the basis for calculating the drug’s intrinsic dissolution rate. Eino then explained to me his theory that the rate of gastrointestinal absorption of most drugs, when administered in solid form as tablets or capsules, is determined by their rate of dissolution in gastrointestinal fluids. He subsequently extended his studies to theophylline derivatives and certain antibiotics before eventually turning to research in pharmacokinetics. When I joined the faculty of the University of Buffalo (now The State University of New York University at Buffalo) in 1958, I decided to extend this work from drug pellets to conventional tablets. As the first step, it was necessary to develop a dissolution test procedure suitable for such tablets. I had the University’s glass blower construct a 400 ml capacity double-walled Griffin beaker with inlet and outlet to permit circulation of temperature-controlled water through the jacket. An electronic controlled speed stirrer and a polyethylene-coated propeller completed the apparatus. An extensive review of the literature on gastric motility revealed to me that mixing of stomach content was very mild such that different foods ingested consecutively tended to remain in layers until emptied from the stomach. To relate this to the behavior of tablets, I prepared some rapidly disintegrating tablets containing barium sulfate as a radio-opaque indicator and arranged with a medical colleague for serial X-rays after I had taken such a tablet. The images, reproduced in reference 1, showed that the tablet disintegrated promptly in the stomach and remained there as an aggregate rather than as a dispersion of granules and/or particles throughout the gastric fluid. Consequently, I decided to keep the agitation intensity (stirring rate) very low, just sufficient to attain homogeneity in the dissolution medium for serial sampling. We later conceived of an indirect way to determine the stirring rate equivalent in our in vitro system to the typical in vivo conditions (2). The result turned out to be very close to the stirring rate that I had selected initially. Moreover, we could demonstrate that stirring rates too fast or too slow could produce very misleading results in comparative dissolution studies (1,2). Our beaker dissolution test eventually evolved into the widely used Dissolution Method 2 of the United States Pharmacopeia (USP). Under conditions of low intensity stirring in our dissolution test, tablets typically form a small mound or aggregate after disintegration. This becomes important for tablets containing two or more interacting components. We showed that aspirin in tablets containing an antacid dissolved much more rapidly than aspirin in tablets without antacid upon mild stirring and that these differences disappeared totally when the dissolution medium is stirred more rapidly so that all the particles are completely dispersed and individually separated in the dissolution medium (2). The pH of the microenvironment of the aggregate of an aspirin–antacid mixture as determined with microelectrodes was several units higher than that in the bulk dissolution medium. We determined the in vitro dissolution rate of aspirin from three different commercial plain aspirin tablet products as well as of calcium aspirin and an aspirin-antacid product and tested their absorption rate in a total of 24 volunteers by a urinary excretion test method. The results revealed a strong positive correlation between dissolution rate and absorption rate (3), the first such published correlation. On the other hand, there was no positive correlation between the disintegration rate of the tablets and their relative absorption rate; the correlation in this particular case was actually negative. I recommended that the USP disintegration test be replaced by a dissolution test but that took several years to come about. In the meantime, we continued our studies of drug dissolution, including the role of pharmaceutical formulation variables, tablet lubricants and film formation. All this is necessary background for describing the genesis of the manuscript that is the focus of this article. During the 1950s, there was an intense commercial competition between the manufacturers of the two leading brands of aspirin tablets, one plain and the other “buffered”, i.e. with antacid. The “twice as fast” claims for the latter stimulated a number of clinical studies resulting in different conclusions that were of sufficient general interest to achieve publication in a premier medical journal, the New England Journal of Medicine (NEJM). At the same time, there was considerable discussion in the literature about the causes of gastrointestinal intolerance and mucosal bleeding associated with aspirin, again with substantial diversity of opinions. Then appeared a report by Rubin et al. in a 1959 issue of the NEJM which was thought to have resolved the plain vs. buffered aspirin controversy: it was found that buffered aspirin had no effect on intragastric pH as determined by inserting an electrode into the stomach of volunteer subjects. Upon reading this report, I decided to set aside for a while my work on several manuscripts describing our dissolution research to prepare a paper that presents (a) the concept of dissolution rate limited gastrointestinal drug absorption and the role of pharmaceutical formulation in this process as applied to aspirin and (b) my analysis of the literature demonstrating that aspirin-induced gastric mucosal damage produced by aspirin is largely a local rather than a systemic effect and that it would be affected by the dosage form in which it is administered. The concept of the microenvironment of dissolving drug aggregates was presented to explain the observations by Rubin et al. This manuscript was accepted for publication in NEJM and appeared in 1960 (4). Even though we subsequently published several other papers in NEJM, I remember this one with particular pleasure, for several reasons. To put the paper in a historic perspective, it was written before the terms bioavailability, bioequivalence, and biopharmaceutics were coined and their concepts and significance were generally appreciated. This was the first manuscript I published after joining the faculty of the University of Buffalo where I remained for about 40 years. My co-author was an undergraduate research participant who with several other undergraduates was involved in my dissolution research as part of a successful program that I started at Buffalo to interest some of our best students in graduate study. The NEJM paper gave me an opportunity to introduce an important concept of pharmaceutical science to a wide readership of physicians at a time when the role of pharmaceutics, unlike that of medicinal chemistry, was not generally appreciated. Finally, I must own up to the fact that the NEJM paper was not my first publication on aspirin. The first one was published in 1958 in the Practical Edition of the A.Ph.A. Journal and was co-authored by fellow undergraduate Rod Jones, describing our independent development of a constitutable aspirin suspension of extended stability suitable for pediatric use. Publication of this work without a faculty co-author caused a bit of commotion at the University of California. My subsequent research activities followed a more conventional path, largely with NIH support. Aspirin and the salicylates in general continued to engage my interest and efforts for much of the next 20 years. Together with students and clinical collaborators, we elucidated the nonlinear pharmacokinetics of salicylate in humans (the only other saturable pharmacokinetics known at that time was that of ethanol), determined the effect of age from newborns to the elderly and of renal failure on salicylate pharmacokinetics, studied the influence of pharmaceutical dosage form on aspirin-induced gastrointestinal blood loss in humans, demonstrated the efficacy of early administration of activated charcoal for managing acute overdosing of aspirin, and characterized some drug interactions with salicylate. All this was a great learning experience and a lot of fun.

Background Symptomatic treatment of Parkinson's disease (PD) is based on the dopamine precursor levodopa. Levodopa is only absorbed in the small intestine, where transit time is approximately 3 h and the plasma elimination half-life is short. Therefore, gastric emptying is a major determining factor for onset of symptom relief. Objective Gastric emptying is delayed in PD, thereby causing motor fluctuations such as 'delayed on'. Factors that further slow gastric emptying should be recognised and eliminated if possible. Methods A literature search was performed with the aim to cover the area of irregular gastrointestinal drug absorption in PD. Results/conclusion Methods for facilitation of pyloric passage or increase of bioavailability are discussed. Development of new drug formulations and alternative routes of administration is ongoing. Transdermal patches and pumps for subcutaneous or intraduodenal infusions are available for patients with severe fluctuations due to erratic gastric emptying.

Pharmacokinetics is a discipline aimed at predicting the best dosage and dosing regimen for each single drug in order to ensure and maintain therapeutically effective concentrations at the action sites. In cardiac critical care patients, various pathophysiological conditions may significantly alter the pharmacokinetic behaviour of drugs. Gastrointestinal drug absorption may be erratic and unpredictable in the early postoperative period, and so patients may be unresponsive to oral therapy; thus the intravenous route should be preferred for life-saving drugs whenever feasible. Variations in the extracellular fluid content as a response to the trauma of surgery and the fluid load or significant drug loss through thoracic drainages may significantly lower plasma concentrations of extracellularly distributed hydrophilic antimicrobials (β-lactams, aminoglycosides and glycopeptides). Drug metabolism may be altered by the systemic inflammatory response and/or multiple organ failure and/or drug-drug pharmacokinetic interactions that can potentially occur during polytherapy, especially in immunosuppressed cardiac transplant patients. Instability of renal function may promote significant changes in body fluid concentrations of renally eliminated drugs, even in a brief period of hours. Finally, the application of extracorporeal circulation by means of cardiopulmonary bypass may significantly alter the disposition of several drugs during the operation because of acute haemodilution, hypoalbuminaemia, hypothermia and/or adsorption to the bypass equipment. Accordingly, to avoid either overexposure and the consequent increased risk of toxicity or underexposure and the consequent risk of therapeutic failure in critically ill cardiac patients, the dosing regimens of several drugs are expected to be significantly different from those suggested for clinically stable patients. Additionally, therapeutic drug monitoring may be helpful in the management of drug therapy and should be routinely used to guide individualized dose adjustments for (i) immunosuppressants whenever cytochrome P450 3A4 isoenzyme inhibitors (e.g. macrolide antibacterials, azole antifungals) or inducers (e.g. rifampicin [rifampin]) are added to or withdrawn from the regimen; and (ii) glycopeptide and aminoglycoside antibacterials whenever haemodynamically active agents (such as dopamine, dobutamine and furosemide [frusemide]) are added to or withdrawn from the regimen, and also whenever significant changes of haemodynamics and/or of renal function occur. © 2008 Adis Data Information BV. All rights reserved.

Promoted Gastrointestinal Drug Absorption Gastrointestinal Anatomy, Physiology and Permeation Pathways Abraham Rubinstein Enhancers for Enteral Delivery of Macromolecules with Emphasis on Surfactants Biana Godin and Elka Touitou Improvement of Oral Drug Absorption by Chitosan and its Derivatives Hiraku Onishi and Yoshiharu Machida Targeted GI Delivery David R. Friend Inhibition of Enzymes and Secretory Transport Martin Werle and Andreas Bernkop-Schnurch Enhanced Gastrointestinal Absorption of Lipophilic Drugs Arik Dahan and Amnon Hoffman Promoted Rectal Absorption Permeation Pathway in Rectal Absorption Yoshiteru Watanabe Cyclodextrins and Other Enhancers in Rectal Delivery Hidetoshi Arima and Kaneto Uekama Enhancement of Buccal and Sublingual Absorption Basic Biopharmaceutics of Buccal and Sublingual Absorptions Priya Batheja, Rashmi Thakur, and Bozena Michniak Chemical Enhancers in Buccal and Sublingual Absorptions John D. Smart Transdermal Enhanced Delivery The Lipid Organization in Stratum Corneum and Model Systems Based on Ceramides Miranda W. de Jager, Maja Ponec, and Joke A. Bouwstra Chemical Permeation Enhancement Adrian C. Williams and Brian W. Barry Vesicular Carriers for Enhanced Delivery through the Skin Elka Touitou and Biana Godin Iontophoresis in Transdermal Delivery B. Mudry, Richard H. Guy, and M. Begona Delgado-Charro Electroporation as a Mode of Skin Penetration Enhancement Michael C. Bonner and Brian W. Barry Ultrasound in Percutaneous Absorption Joseph Kost Combined Chemical and Electroporation Methods of Skin Penetration Enhancement Michael C. Bonner and Brian W. Barry Stratum Corneum Bypassed or Removed James C. Birchall Nasal Absorption Optimization Physiological Factors Affecting Nasal Drug Delivery Sian Tiong Lim, Ben Forbes, Marc B. Brown, and Gary P. Martin Nasal Delivery of Peptide Drugs Dennis J. Pillion, John J. Arnold, and Elias Meezan Drug Absorption from Vagina and Uterus Vagina and Uterus as Drug-Absorbing Organs R. Karl Malcolm, Stephen D. McCullagh, Ryan J. Morrow, and A. David Woolfson Strategies to Improve Systemic and Local Availability of Drugs Administered via Vaginal Route Giuseppina Sandri, Silvia Rossi, Franca Ferrari, Maria Cristina Bonferoni, and Carla Caramella Systemic Absorption through the Ocular Route Eye Structure and Physiological Functions Clive G. Wilson, Ekaterina M. Semenova, Patrick M. Hughes, and Orest Olejnik Drug Delivery Systems for Enhanced Ocular Absorption Muhammad Abdulrazik, Francine Behar-Cohen, and Simon Benita Ocular Penetration Enhancers Indu Pal Kaur and Anupam Batra Iontophoresis for Ocular Drug Delivery Esther Eljarrat-Binstock, Joseph Frucht-Pery, and Abraham J. Domb Drug Delivery to the Central Nervous System Structure and Function of the Blood-Brain Barrier David J. Begley Strategies to Overcome the Blood-Brain Barrier Elena V. Batrakova and Alexander V. Kabanov

The aim of this study was to assess the feasibility of using oral modified-release formulations for the purposes of site-specific targeting and regional drug absorption assessment in man. An immediate release pellet formulation containing ranitidine as the model drug of choice for the study was fabricated by extrusion-spheronisation, and then film coated with either the enteric polymer polyvinyl acetate phthalate or the bacteria-degradable polymer amylose, in combination with ethylcellulose, to effect drug release within the small intestine and colon, respectively. Optimised formulations were evaluated in vivo in ten healthy volunteers, who each received, on four separate occasions, the immediate release, small intestinal release and colonic release formulations (each equivalent to 150mg ranitidine), and an intravenous injection of ranitidine (equivalent to 50mg ranitidine). Blood samples were collected and assessed for ranitidine concentration, and radiolabelled placebo pellets were co-administered with the coated ranitidine pellets to monitor their gastrointestinal transit using a gamma camera. Ranitidine was rapidly released and absorbed from the immediate release formulation, whereas the enteric formulation (10% coat weight gain) delayed drug release until some or all of the pellets had emptied into the small intestine. The amylose-ethylcellulose coated formulation (coat ratio 1:3, coat weight gain 25%) retarded ranitidine release until the pellets had reached the colon. The mean absolute bioavailability of ranitidine from the immediate release, small intestinal release and colonic release formulations were 50.6, 46.1 and 5.5%, respectively. These data are in general agreement to those obtained from a previous regional intubation study. The present study therefore demonstrates the practical potential of utilising a non-invasive, formulation-based approach to assess drug absorption from different regions of the human gastrointestinal tract.

In this review, the gross physiology of the gastrointestinal tract of dogs is compared with that of humans, particularly as it pertains to drug absorption and dosage-form performance. Gastrointestinal (GI) motility and pH are the main parameters considered. Although similar motility patterns and pH profiles prevail in the two species for the most part, there are some differences that could affect the time profile and extent of drug absorption. These include slower gastric emptying in the fed state, faster small intestine transit, and higher and more variable intestinal pH in dogs compared with humans. An attempt is made to identify drug and dosage-form properties that would lead to differences in drug absorption in the two species, e.g., drug physicochemical properties, dosage-form size, and pH dependency of dosage-form release characteristics.

Antacids interfere with gastrointestinal drug absorption by either increasing or decreasing the rate at which a drug is absorbed, or the total quantity absorbed. Antacids influence drug absorption by alteration of ionization state or solubility, factors dependent upon pH. Antacids also delay gastric emptying and are capable of chelation and adsorption with susceptible products. Many of these factors participate to produce the effect on gastrointestinal drug absorption in individual patients.

A computer simulation model of transport of material along the small intestine is proposed. The model is developed by considering a succession of boluses, created by stomach emptying, which proceed by discontinuous jumps along the small intestine. During a jump material can be exchanged between adjacent boluses to simulate longitudinal mixing. The model is tested by comparison of simulated distribution profiles of test markers with reported distribution of non-absorbable radioactive test markers in the small intestine of the rat and with colonic arrival times in man, resulting in good agreement between simulations and experimental data.

The literature concerning the influence of food, and also fluid volumes, on drug absorption is reviewed. In most cases, the absorption of drugs from the gastrointestinal tract is reduced or delayed by food. However, some drugs are unaffected by food, while the absorption of a small number of drugs is increased. Observed effects of food on drug absorption are the net result of various factors, including the influence of food on gastrointestinal physiology and also physicochemical interactions between drugs, drug dosage forms, and dietary components. The intensity of food-drug interactions may be influenced by the type of food and by the time interval between eating and drug administration. Large coadministered fluid volumes tend to promote drug absorption. The clinical significance of changes in drug bioavailability due to these factors is discussed.

There has been considerable interest in the past fifteen years in determining the influence of food and diet on gastrointestinal drug absorption. Welling21 has recently presented a comprehensive and critical review of these efforts. In general, food reduces the absorption rate of drugs from the gastrointestinal tract but in most instances has little influence on the extent of absorption. Such an effect is clinically significant for sedative-hypnotics and for other drugs where a prompt response is desired but is probably of little concern in most other cases. On the other hand, food has been found to substantially reduce the extent of absorption of certain drugs, including many antibiotics. This type of food effect often occurs with drugs with poor permeability characteristics that are incompletely absorbed even by fasting patients. Continual administration of such drugs with meals would result in lower steady-state drug concentrations in plasma than would be found were the drug to be given under fasting conditions.

Segmental differences in transmucosal fluid movement and their effects on gastrointestinal drug absorption in rabbits were studied with aspirin as an acidic drug and metoclopramide as a basic compound. The segments used were stomach, duodenum, jejunum and ileum. The ligation method was employed in the stomach study and other segments were studied by using an in situ loop method. All segments were investigated simultaneously. Segmental differences in transmucosal fluid movement was statistically observed with a one-way analysis of variance, although the initial drug solutions were adjusted to isotonicity. The net fluid absorption was increased as the distance from the mouth increased. A good positive correlation between transmucosal fluid movement and drug absorption was found in both drug studies. We conclude that segmental differences in drug absorption are partly dependent upon the transmucosal fluid movement in each gastrointestinal segment.

Experiments were made on the effect of particle size on gastrointestinal drug absorption in the rabbit and its relation to solubility using powder drugs, in a series of solubility ranging from 1 to 25 mg/ml at 37°in suspension, and a consideration was made on the relationship between solubility and bioavailability on the basis of particle size, with following results. 1) The blood concentration-time curves at the particle size up to some sizes showed a similar time course curve obtained with an aqueous solution of each drug. Provided that the maximum particle size limit which described a time course curve similar to that of solution was the critical particle size (CPS), effect of particle size on the blood level appeared above the CPS of a drug. The CPS depended mainly on the solubility with slight relation of individual absorption rate of each drug solution and increased linearly with an increase in solubility. The extent of availability for different particle size grades was almost constant in each powder drug. 2) General consideration was made on the relationship between solubility and bioavailability on the basis of a particle size. This relation may vary with other factors, especially, dosage forms such as tablet, capsule, etc., physiological factors, and individual properties of the drugs. However, this relation would be useful as a temporary standard as for considering the relationship between solubility and bioavailability on the basis of particle size.

A method is reported for studying gastrointestinal drug absorption from isolated gut segments of the anesthetized rat in situ. The experimental technique is simple and utilizes readily available laboratory equipment. The results are closely reproducible and yield absorption rates which are realistic in terms of the known absorption behavior of drugs in humans and intact animals. Disappearance of the drugs from the lumen of the small intestine followed apparent first-order kinetics; and the following half-lives were determined at pH 6: aminopyrine, 32 min.; barbital, 19 min.; haloperidol, 24 min.; prochlorperazine, 23 min.; salicylic acid, 8 min,; and sulfaethidole, 32 min. These absorption rates are much faster than those normally observed in in situ intestinal preparations. Absorption rates from rat stomach in situ, and preliminary data showing a relationship between fasting time and intestinal absorption rates in the rat are also presented.

HURWITZ, A., AND DOULL, J. Effect of Irradiation on Gastrointestinal Drug Absorption in Mice and Rats. Radiat. Res. 59, 606-613 (1974). X-irradiation inhibits gastrointestinal absorption of nutrients by damaging the intestinal mucosal cells which actively transport these chemicals. The results of the present study demonstrate that sublethal doses of X-irradiation delay the passive gastrointestinal absorption of an acidic drug, sulfadiazine, and a basic drug, quinine, in mice. This effect is detectable 2 hr after radiation exposure and is most pronounced in the first 3 postirradiation days. Both the magnitude and the duration of the effect are related to the radiation dose (25-300 R in mice and 200-800 R in rats). The effect was not demonstratable when sulfadiazine was given by intraperitoneal or intraduodenal rather than by intragastric administration after which more of the drug was retained in the stomachs of rats irradiated 21 hr earlier. Head irradiation, which is known to delay gastric emptying, lowered blood levels of sulfadiazine after gastric administration, and shielding partially protected against this delayed drug absorption. This effect was most pronounced in whole body irradiated rats. Thus, delayed gastric emptying is the major cause of inhibited gastrointestinal drug absorption in the first 3 days after irradiation