Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions.

To enable more precise prediction of oral drug absorption, an existing physiologically based absorption model was revised. The revised model reflects detailed knowledge of human gastrointestinal (GI) physiology including fluid secretion and absorption, and comprises an elaborate representation of the intestinal mucosa. The alimentary canal from the stomach to the rectum was divided into 12 compartments. A mucosal compartment was added to each luminal segment of the intestine. A training set of 111 passively absorbed drugs with reported fractions of dose absorbed was used to optimize the semiempirical equation, which calculates intestinal permeability coefficients. The model was subsequently integrated into an established physiologically based pharmacokinetic software and validated by prediction of plasma concentration-time profiles of eight test compounds with diverse physicochemical properties. A good correlation between the simulated and experimental fractions of dose absorbed was established for the 111 compounds in the training set. Subsequently, the concentration-time profiles of six out of eight test compounds were predicted with high accuracy. The detailed model for GI transit and absorption presented in this study can help to understand the complex processes of oral absorption better and will be useful during the drug development process.

[1]  Wolfgang Weiss,et al.  A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks , 2011, Front. Physio..

[2]  D M Barends,et al.  Biowaiver monographs for immediate release solid oral dosage forms: furosemide. , 2010, Journal of pharmaceutical sciences.

[3]  Christos Reppas,et al.  Characterization of the Contents of Ascending Colon to Which Drugs are Exposed After Oral Administration to Healthy Adults , 2009, Pharmaceutical Research.

[4]  Sebastian Polak,et al.  Population-Based Mechanistic Prediction of Oral Drug Absorption , 2009, The AAPS Journal.

[5]  D. Barends,et al.  Biowaiver monographs for immediate release solid oral dosage forms: diclofenac sodium and diclofenac potassium. , 2009, Journal of pharmaceutical sciences.

[6]  G. Amidon,et al.  Segmental dependent transport of low permeability compounds along the small intestine due to P-glycoprotein: the role of efflux transport in the oral absorption of BCS class III drugs. , 2009, Molecular pharmaceutics.

[7]  Kairui Feng,et al.  The Simcyp® Population-based ADME Simulator , 2009 .

[8]  Kairui Feng,et al.  The Simcyp population-based ADME simulator. , 2009, Expert opinion on drug metabolism & toxicology.

[9]  V. Lukacova,et al.  Predicting Pharmacokinetics of Drugs Using Physiologically Based Modeling—Application to Food Effects , 2009, The AAPS Journal.

[10]  A. Basit,et al.  Gut instincts: explorations in intestinal physiology and drug delivery. , 2008, International journal of pharmaceutics.

[11]  D. Barends,et al.  Biowaiver monographs for immediate release solid oral dosage forms: aciclovir. , 2008, Journal of pharmaceutical sciences.

[12]  Franco Lombardo,et al.  Measurement of dissociation constants (pKa values) of organic compounds by multiplexed capillary electrophoresis using aqueous and cosolvent buffers. , 2008, Journal of pharmaceutical sciences.

[13]  Neil Parrott,et al.  Applications of physiologically based absorption models in drug discovery and development. , 2008, Molecular pharmaceutics.

[14]  Walter Schmitt,et al.  General approach for the calculation of tissue to plasma partition coefficients. , 2008, Toxicology in vitro : an international journal published in association with BIBRA.

[15]  David S. Wishart,et al.  DrugBank: a knowledgebase for drugs, drug actions and drug targets , 2007, Nucleic Acids Res..

[16]  Walter Schmitt,et al.  Whole body physiologically-based pharmacokinetic models: their use in clinical drug development , 2008, Expert opinion on drug metabolism & toxicology.

[17]  M. Farré,et al.  Study of paracetamol 1-g oral solution bioavailability. , 2008, Methods and findings in experimental and clinical pharmacology.

[18]  J. Dressman,et al.  Towards Quantitative Prediction of Oral Drug Absorption , 2008, Clinical pharmacokinetics.

[19]  D. Otto,et al.  Effect of pH on the solubility and release of furosemide from polyamidoamine (PAMAM) dendrimer complexes. , 2007, International journal of pharmaceutics.

[20]  H Lennernäs,et al.  Intestinal permeability and its relevance for absorption and elimination , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[21]  Theo Dingermann,et al.  Anatomie, Physiologie, Pathophysiologie des Menschen. Von Ernst Mutschler, Hans‐Georg Schaible und Peter Vaupel , 2007 .

[22]  Jochem Alsenz,et al.  Development of a partially automated solubility screening (PASS) assay for early drug development. , 2007, Journal of pharmaceutical sciences.

[23]  M. Jamei,et al.  A Novel Physiologically-Based Mechanistic ModelPredicting Oral Drug Absorption: The Advanced Dissolution, Absorption, and Metabolism (ADAM) Model , 2007 .

[24]  Germán Novoa-Heckel,et al.  Bioavailability of two oral suspension and two oral tablet formulations of acyclovir 400 mg: two single-dose, open-label, randomized, two-period crossover comparisons in healthy Mexican adult subjects. , 2007, Clinical therapeutics.

[25]  Walter Schmitt,et al.  Development of a Physiology-Based Whole-Body Population Model for Assessing the Influence of Individual Variability on the Pharmacokinetics of Drugs , 2007, Journal of Pharmacokinetics and Pharmacodynamics.

[26]  K. Arslan,et al.  A geometric description of human intestine. , 2007, Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia.

[27]  Malcolm Rowland,et al.  Mechanistic Approaches to Volume of Distribution Predictions: Understanding the Processes , 2007, Pharmaceutical Research.

[28]  G. M. Pollack,et al.  Intestinal Absorptive Transport of the Hydrophilic Cation Ranitidine: A Kinetic Modeling Approach to Elucidate the Role of Uptake and Efflux Transporters and Paracellular vs. Transcellular Transport in Caco-2 Cells , 2006, Pharmaceutical Research.

[29]  M. Rowland,et al.  Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. , 2006, Journal of pharmaceutical sciences.

[30]  J. Dressman,et al.  Canine Intestinal Contents vs. Simulated Media for the Assessment of Solubility of Two Weak Bases in the Human Small Intestinal Contents , 2006, Pharmaceutical Research.

[31]  D. Barends,et al.  Biowaiver monographs for immediate release solid oral dosage forms: cimetidine. , 2006, Journal of pharmaceutical sciences.

[32]  David S. Wishart,et al.  DrugBank: a comprehensive resource for in silico drug discovery and exploration , 2005, Nucleic Acids Res..

[33]  E. Persson Drug dissolution under physiologically relevant conditions in vitro and in vivo. , 2006 .

[34]  D. Barends,et al.  Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol). , 2006, Journal of pharmaceutical sciences.

[35]  J. Dressman,et al.  Characterization of the Human Upper Gastrointestinal Contents Under Conditions Simulating Bioavailability/Bioequivalence Studies , 2006, Pharmaceutical Research.

[36]  N. Hosten,et al.  Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging , 2005, Alimentary pharmacology & therapeutics.

[37]  Hans Lennernäs,et al.  The Effects of Food on the Dissolution of Poorly Soluble Drugs in Human and in Model Small Intestinal Fluids , 2005, Pharmaceutical Research.

[38]  L. Wienkers,et al.  Predicting in vivo drug interactions from in vitro drug discovery data , 2005, Nature Reviews Drug Discovery.

[39]  A. Zinsmeister,et al.  Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study. , 2005, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[40]  Malcolm Rowland,et al.  Tissue distribution of basic drugs: accounting for enantiomeric, compound and regional differences amongst beta-blocking drugs in rat. , 2005, Journal of pharmaceutical sciences.

[41]  Jörg Lippert,et al.  From physicochemistry to absorption and distribution: predictive mechanistic modelling and computational tools , 2005, Expert opinion on drug metabolism & toxicology.

[42]  M. Rowland,et al.  Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. , 2005, Journal of pharmaceutical sciences.

[43]  G. Wilkinson,et al.  Drug metabolism and variability among patients in drug response. , 2005, The New England journal of medicine.

[44]  M. Marsh,et al.  Morphometric analysis of small intestinal mucosa IV. Determining cell volumes , 2005, Virchows Archiv A.

[45]  John Gutknecht,et al.  Permeability of small nonelectrolytes through lipid bilayer membranes , 2005, The Journal of Membrane Biology.

[46]  Amin Rostami-Hodjegan,et al.  Cytochrome P450 3A expression and activity in the human small intestine , 2004, Clinical pharmacology and therapeutics.

[47]  Walter Schmitt,et al.  A physiological model for the estimation of the fraction dose absorbed in humans. , 2004, Journal of medicinal chemistry.

[48]  L. Berezhkovskiy,et al.  Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination. , 2004, Journal of pharmaceutical sciences.

[49]  M. Machida,et al.  Biopharmaceutics Classification by High Throughput Solubility Assay and PAMPA , 2004, Drug development and industrial pharmacy.

[50]  W. Schmitt,et al.  A Physiologic Model for Simulating Gastrointestinal Flow and Drug Absorption in Rats , 2003, Pharmaceutical Research.

[51]  Jörg Keldenich,et al.  Multilamellar Liposomes and Solid-Supported Lipid Membranes (TRANSIL): Screening of Lipid-Water Partitioning Toward a High-Throughput Scale , 2001, Pharmaceutical Research.

[52]  D. Fleisher,et al.  Regulation of Paracellular Absorption of Cimetidine and 5-Aminosalicylate in Rat Intestine , 1999, Pharmaceutical Research.

[53]  B. Müller,et al.  Drug Liposome Partitioning as a Tool for the Prediction of Human Passive Intestinal Absorption , 1999, Pharmaceutical Research.

[54]  Xiaoling Li,et al.  Transbuccal Delivery of Acyclovir: I. In Vitro Determination of Routes of Buccal Transport , 1998, Pharmaceutical Research.

[55]  S. Stavchansky,et al.  Estimation of the Relative Contribution of the Transcellular and Paracellular Pathway to the Transport of Passively Absorbed Drugs in the Caco-2 Cell Culture Model , 1997, Pharmaceutical Research.

[56]  Shiyin Yee,et al.  In Vitro Permeability Across Caco-2 Cells (Colonic) Can Predict In Vivo (Small Intestinal) Absorption in Man—Fact or Myth , 1997, Pharmaceutical Research.

[57]  Kristina Luthman,et al.  Polar Molecular Surface Properties Predict the Intestinal Absorption of Drugs in Humans , 1997, Pharmaceutical Research.

[58]  H. Lennernäs,et al.  Characterization of Fluids from the Stomach and Proximal Jejunum in Men and Women , 1997, Pharmaceutical Research.

[59]  Liang-Shang Gan,et al.  Mechanism of Intestinal Absorption of Ranitidine and Ondansetron: Transport Across Caco-2 Cell Monolayers , 1993, Pharmaceutical Research.

[60]  T. Xiang,et al.  The relationship between permeant size and permeability in lipid bilayer membranes , 1993, The Journal of Membrane Biology.

[61]  J. Dressman,et al.  Upper Gastrointestinal (GI) pH in Young, Healthy Men and Women , 1990, Pharmaceutical Research.

[62]  T. Eide A morphometrical analysis of dysplasia in small adenomas of the large instestine , 1987, Virchows Archiv A.

[63]  M. Rawlins,et al.  Pharmacokinetics of paracetamol (acetaminophen) after intravenous and oral administration , 1977, European Journal of Clinical Pharmacology.

[64]  A. Rosén,et al.  On the fate of furosemide in man , 1975, European Journal of Clinical Pharmacology.

[65]  B N S Bhatnagar,et al.  Study on the anatomical dimensions of the human sigmoid colon , 2004, Clinical anatomy.

[66]  Leslie Z. Benet,et al.  Predicting Drug Disposition via Application of BCS: Transport/Absorption/ Elimination Interplay and Development of a Biopharmaceutics Drug Disposition Classification System , 2004, Pharmaceutical Research.

[67]  J. Lötsch,et al.  Population Pharmacokinetics of Fast Release Oral Diclofenac in Healthy Volunteers: Relation to Pharmacodynamics in an Experimental Pain Model , 2004, Pharmaceutical Research.

[68]  M. Marsh,et al.  Morphometric analysis of small intestinal mucosa , 2004, Virchows Archiv.

[69]  A. Staib,et al.  Measurement of theophylline absorption from different regions of the gastro-intestinal tract using a remote controlled durg delivery device , 2004, European Journal of Clinical Pharmacology.

[70]  M. Lind,et al.  Plasma and salivary pharmacokinetics of caffeine in man , 2004, European Journal of Clinical Pharmacology.

[71]  R. Levy,et al.  Kinetics of phenobarbital in normal subjects and epileptic patients , 2004, European Journal of Clinical Pharmacology.

[72]  J. Blanchard,et al.  The absolute bioavailability of caffeine in man , 2004, European Journal of Clinical Pharmacology.

[73]  P. G. Welling,et al.  The pharmacokinetics of diclofenac sodium following intravenous and oral administration , 2004, European Journal of Clinical Pharmacology.

[74]  Christos Reppas,et al.  Dissolution Testing as a Prognostic Tool for Oral Drug Absorption: Immediate Release Dosage Forms , 2004, Pharmaceutical Research.

[75]  Walter Schmitt,et al.  PK-Sim®: a physiologically based pharmacokinetic ‘whole-body’ model , 2003 .

[76]  Kevin C. Johnson,et al.  Dissolution and Absorption Modeling: Model Expansion to Simulate the Effects of Precipitation, Water Absorption, Longitudinally Changing Intestinal Permeability, and Controlled Release on Drug Absorption , 2003, Drug development and industrial pharmacy.

[77]  J. Valentin Basic anatomical and physiological data for use in radiological protection: reference values , 2002, Annals of the ICRP.

[78]  T. Wiedmann,et al.  Examination of the solubilization of drugs by bile salt micelles. , 2002, Journal of pharmaceutical sciences.

[79]  Patrick Poulin,et al.  Prediction of pharmacokinetics prior to in vivo studies. II. Generic physiologically based pharmacokinetic models of drug disposition. , 2002, Journal of pharmaceutical sciences.

[80]  Patrick Poulin,et al.  Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution. , 2002, Journal of pharmaceutical sciences.

[81]  B Agoram,et al.  Predicting the impact of physiological and biochemical processes on oral drug bioavailability. , 2001, Advanced drug delivery reviews.

[82]  C. Porter,et al.  Intestinal lymphatic drug transport: an update. , 2001, Advanced drug delivery reviews.

[83]  A. Eckert,et al.  Solid-supported lipid membranes as a tool for determination of membrane affinity: high-throughput screening of a physicochemical parameter. , 2001, Journal of pharmaceutical sciences.

[84]  F. Theil,et al.  Prediction of adipose tissue: plasma partition coefficients for structurally unrelated drugs. , 2001, Journal of pharmaceutical sciences.

[85]  J. DeSesso,et al.  Anatomical and physiological parameters affecting gastrointestinal absorption in humans and rats. , 2001, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[86]  J. Legendre,et al.  Determination of the Aqueous Solubility of Drugs Using a Convenient 96-Well Plate-Based Assay , 2001, Drug development and industrial pharmacy.

[87]  J. Cummings The Effect of Dietary Fiber on Fecal Weight and Composition , 2001 .

[88]  M. Wilson,et al.  Regulation of intestinal blood flow. , 2000, The Journal of surgical research.

[89]  W. Krause,et al.  Brunner's glands: a structural, histochemical and pathological profile. , 2000, Progress in histochemistry and cytochemistry.

[90]  F. Theil,et al.  A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. , 2000, Journal of pharmaceutical sciences.

[91]  G. Shorten,et al.  Cisapride does not alter gastric volume or pH in patients undergoing ambulatory surgery , 1999, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[92]  D. Flanagan,et al.  General solution for diffusion-controlled dissolution of spherical particles. 1. Theory. , 1999, Journal of pharmaceutical sciences.

[93]  J. Fallingborg,et al.  Intraluminal pH of the human gastrointestinal tract. , 1999, Danish medical bulletin.

[94]  T. Baillie,et al.  Is the role of the small intestine in first-pass metabolism overemphasized? , 1999, Pharmacological reviews.

[95]  Sean C. Sweetman,et al.  Martindale: The Complete Drug Reference , 1999 .

[96]  D. Fleisher,et al.  Drug, Meal and Formulation Interactions Influencing Drug Absorption After Oral Administration , 1999, Clinical pharmacokinetics.

[97]  M. Rowland,et al.  Modulation of the permeability of H2 receptor antagonists cimetidine and ranitidine by P-glycoprotein in rat intestine and the human colonic cell line Caco-2. , 1999, The Journal of pharmacology and experimental therapeutics.

[98]  Press,et al.  Gastrointestinal pH profiles in patients with inflammatory bowel disease , 1998, Alimentary pharmacology & therapeutics.

[99]  Peter C. Jurs,et al.  Prediction of Human Intestinal Absorption of Drug Compounds from Molecular Structure , 1998, J. Chem. Inf. Comput. Sci..

[100]  H Lennernäs,et al.  Human intestinal permeability. , 1998, Journal of pharmaceutical sciences.

[101]  K Gubernator,et al.  Physicochemical high throughput screening: parallel artificial membrane permeation assay in the description of passive absorption processes. , 1998, Journal of medicinal chemistry.

[102]  P. Vernia,et al.  Quantitative analysis of stool losses in adult celiac disease: use of near-infrared analysis reconsidered. , 1998, Scandinavian journal of gastroenterology.

[103]  D. Shen,et al.  Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. , 1997, The Journal of pharmacology and experimental therapeutics.

[104]  D. R. L. Snipes Intestinal Absorptive Surface in Mammals of Different Sizes , 1997, Advances in Anatomy Embryology and Cell Biology.

[105]  N. Davies,et al.  Clinical Pharmacokinetics of Diclofenac , 1997, Clinical pharmacokinetics.

[106]  T. Gray,et al.  Migration of human intestinal lamina propria lymphocytes, macrophages and eosinophils following the loss of surface epithelial cells , 1997, Clinical and experimental immunology.

[107]  J. Cummings,et al.  The large intestine in nutrition and disease. , 1997 .

[108]  J. Dressman,et al.  Physiochemical and physiological mechanisms for the effects of food on drug absorption: the role of lipids and pH. , 1997, Journal of pharmaceutical sciences.

[109]  G. Grass,et al.  Simulation models to predict oral drug absorption from in vitro data , 1997 .

[110]  Lawrence X. Yu,et al.  Compartmental transit and dispersion model analysis of small intestinal transit flow in humans , 1996 .

[111]  G L Amidon,et al.  Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. , 1996, Advanced drug delivery reviews.

[112]  S. Skinner,et al.  The microvascular structure of the normal colon in rats and humans. , 1996, The Journal of surgical research.

[113]  C. Williams,et al.  Intraoperative measurement of colonic anatomy and attachments with relevance to colonoscopy , 1995, The British journal of surgery.

[114]  T. Kararli Comparison of the gastrointestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals , 1995, Biopharmaceutics & drug disposition.

[115]  H. Mascher,et al.  Pharmacokinetics and bioavailability of different formulations of aciclovir. , 1995, Arzneimittel-Forschung.

[116]  A. Rubinstein Approaches and opportunities in colon-specific drug delivery. , 1995, Critical reviews in therapeutic drug carrier systems.

[117]  M. Camilleri,et al.  Ascending colon response to feeding: evidence for a 5-hydroxytryptamine-3 mechanism. , 1995, Scandinavian journal of gastroenterology.

[118]  J. Fell,et al.  Targeting drugs to the colon: delivery systems for oral administration. , 1994, Journal of drug targeting.

[119]  A. Ensari,et al.  Morphometric analysis of intestinal mucosa. V. Quantitative histological and immunocytochemical studies of rectal mucosae in gluten sensitivity. , 1993, Gut.

[120]  R. Schmidt,et al.  Physiologie des Menschen , 1993, Springer-Lehrbuch.

[121]  S A Bingham,et al.  Fecal weight, colon cancer risk, and dietary intake of nonstarch polysaccharides (dietary fiber) , 1992, Gastroenterology.

[122]  P. Kelly,et al.  Ageing and duodenal morphometry. , 1992, Journal of clinical pathology.

[123]  D F Evans,et al.  Gastrointestinal intraluminal pH in normal subjects and those with colorectal adenoma or carcinoma. , 1990, Gut.

[124]  K. Ono,et al.  Ultrastructure of surface epithelial cells of the normal human rectum. , 1990, Zeitschrift fur mikroskopisch-anatomische Forschung.

[125]  L. A. Christensen,et al.  pH‐Profile and regional transit times of the normal gut measured by a radiotelemetry device , 1989, Alimentary pharmacology & therapeutics.

[126]  D. Campoli-Richards,et al.  Acyclovir. An updated review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy. , 1989, Drugs.

[127]  J. Hardy,et al.  The effect of eating on transit through the small intestine. , 1989, Nuclear medicine communications.

[128]  L. Schiller,et al.  Quantification of colonic lamina propria cells by means of a morphometric point-counting method. , 1988, Gastroenterology.

[129]  P. Degen,et al.  Pharmacokinetics of diclofenac and five metabolites after single doses in healthy volunteers and after repeated doses in patients. , 1988, Xenobiotica; the fate of foreign compounds in biological systems.

[130]  Clive G. Wilson,et al.  The influence of food on the absorption of acyclovir: a pharmacokinetic and scintigraphic assessment , 1987 .

[131]  S F Phillips,et al.  Simplified assessment of segmental colonic transit. , 1987, Gastroenterology.

[132]  J. Maltby,et al.  Preoperative Oral Fluids: Is a Five‐hour Fast Justified Prior to Elective Surgery? , 1986, Anesthesia and analgesia.

[133]  I. Beck,et al.  Arteriolar, capillary, and shunt flow gradients along the intestine in relation to the weight distribution of the mucosa, submucosa, and muscularis--a microsphere study. , 1986, Canadian journal of physiology and pharmacology.

[134]  S. Davis,et al.  Alimentary tract andpancreas Transit ofpharmaceutical dosage forms through the , 1986 .

[135]  W. Stigelman,et al.  Goodman and Gilman's the Pharmacological Basis of Therapeutics , 1986 .

[136]  F. Bendtsen,et al.  Intraluminal pH in the stomach, duodenum, and proximal jejunum in normal subjects and patients with exocrine pancreatic insufficiency. , 1986, Gastroenterology.

[137]  N. Kaneniwa,et al.  Study of the absorption site of cimetidine. , 1986, Journal of pharmacobio-dynamics.

[138]  G. Corazza,et al.  Ageing and small-bowel mucosa: a morphometric study. , 1986, Gerontology.

[139]  G Levy,et al.  Renal clearance and serum protein binding of acetaminophen and its major conjugates in humans. , 1984, Journal of pharmaceutical sciences.

[140]  A. Straughn,et al.  Absorption of phenobarbital from tablets and elixir. , 1984, Journal of Pharmacy and Science.

[141]  R. McCallum,et al.  Scintigraphic determination of small intestinal transit time of water in man , 1984 .

[142]  R. Stenling,et al.  Surface ultrastructure of the small intestine mucosa in healthy children and adults: a scanning electron microscopic study with some methodological aspects. , 1984, Ultrastructural pathology.

[143]  A. Staib,et al.  A cross-over study of oral and intravenous administration of theophylline in male volunteers. Absolute bioavailability of theophylline tablets. , 1984, Arzneimittel-Forschung.

[144]  A. Somogyi,et al.  Clinical Pharmacokinetics of Cimetidine , 1983, Clinical pharmacokinetics.

[145]  P. de Miranda,et al.  Pharmacokinetics of acyclovir after intravenous and oral administration. , 1983, The Journal of antimicrobial chemotherapy.

[146]  J. Blanchard Protein binding of caffeine in young and elderly males. , 1982, Journal of pharmaceutical sciences.

[147]  J. Massarella,et al.  Disposition and absolute bioavailability of furosemide in healthy males. , 1982, Journal of pharmaceutical sciences.

[148]  B. Trump,et al.  Human large intestinal epithelium: light microscopy, histochemistry, and ultrastructure. , 1982, Human pathology.

[149]  J. Clements,et al.  Clinical Pharmacokinetics of Paracetamol , 1982, Clinical pharmacokinetics.

[150]  J. Longstreth,et al.  Pharmacokinetics and tolerance of acyclovir, a new anti-herpesvirus agent, in humans , 1982, Antimicrobial Agents and Chemotherapy.

[151]  D. Perrier,et al.  Phenobarbital Pharmacokinetics and Bioavailability in Adults , 1982, Journal of clinical pharmacology.

[152]  K. Hoppe Physiologie des Menschen. Herausgegeben von R. F. Schmidt und G. THEWS. 20. neu bearbeitete Auflage, XXV und 798 Seiten, 569 Abb. und 73 Tab. Springer‐Verlag, Berlin, Heidelberg, New York 1980. Preis: 98,— DM , 1981 .

[153]  G. Corazza,et al.  Gluten sensitivity of small intestinal mucosa in vitro: quantitative assessment of histologic change. , 1981, Gastroenterology.

[154]  G. Slavin,et al.  Measurement in jejunal biopsies by computer-aided microscopy. , 1980, Journal of clinical pathology.

[155]  M. Cohen,et al.  Sieving of solid food by the canine stomach and sieving after gastric surgery. , 1979, Gastroenterology.

[156]  Johnson Va The pharmacokinetics and metabolism of diclofenac sodium (Voltarol) in animals and man. , 1979, Rheumatology and rehabilitation.

[157]  V. John,et al.  The pharmacokinetics and metabolism of diclofenac sodium (Voltarol) in animals and man. , 1979, Rheumatology and rehabilitation.

[158]  J. Bond,et al.  The effects of feeding on blood flow to the stomach, small bowel, and colon of the conscious dog. , 1979, The Journal of laboratory and clinical medicine.

[159]  L F Prescott,et al.  Kinetics of acetaminophen absorption and gastric emptying in man , 1978, Clinical pharmacology and therapeutics.

[160]  R. Ogilvie Clinical Pharmacokinetics of Theophylline , 1978, Clinical pharmacokinetics.

[161]  W. J. Westlake,et al.  Bioavailability of cimetidine in man , 1978 .

[162]  H. McClure,et al.  The Digestive System , 1978 .

[163]  L. Hendeles,et al.  Absolute bioavailability of oral theophylline. , 1977, American journal of hospital pharmacy.

[164]  L. Hultén,et al.  Sympathetic nervous control of intramural blood flow in the feline and human intestines. , 1977, Gastroenterology.

[165]  V. Mirkovitch,et al.  Functional and structural characteristics of the jejunum and ileum in the dog and the rat. , 1977, Digestion.

[166]  J. Cummings Absorption and secretion by the colon. , 1975, Gut.

[167]  Cerda Jj,et al.  Lipids and other components of human jejunal and ileal mucosa. , 1975 .

[168]  J. N. Hunt,et al.  The volume and energy content of meals as determinants of gastric emptying. , 1975, The Journal of physiology.

[169]  J. Rabinowitz,et al.  Lipids and other components of human jejunal and ileal mucosa. , 1975, Research communications in chemical pathology and pharmacology.

[170]  F. Moll Lehrbuch der Pharmazeutischen Technologie. Von R. Voigt. 784 S., 263 Abb., 111 Tab. VEB Volk und Gesundheit, Berlin 1973. Preis: M 63,– , 1974 .

[171]  P. Tothill,et al.  The dependence of paracetamol absorption on the rate of gastric emptying , 1973, British journal of pharmacology.

[172]  A. Bangham,et al.  Diffusion of Small Non-Electrolytes across Liposome Membranes , 1972, Nature.

[173]  A. R. Cooke,et al.  Emptying and absorption of caffeine from the human stomach. , 1971, Gastroenterology.

[174]  K. Diem Documenta Geigy Scientific Tables , 1970 .

[175]  W. R. Lieb,et al.  Biological Membranes behave as Non-porous Polymeric Sheets with Respect to the Diffusion of Non-electrolytes , 1969, Nature.

[176]  S. K. Kim Small intestine transit time in the normal small bowel study. , 1968, The American journal of roentgenology, radium therapy, and nuclear medicine.

[177]  N. Hightower The digestive system. , 1962, Annual review of physiology.

[178]  D. Blankenhorn,et al.  Measurement of the human intestinal length in vivo and some causes of variation. , 1956, Gastroenterology.

[179]  J. N. Hunt,et al.  The influence of volume on gastric emptying , 1954, The Journal of physiology.

[180]  J. Axelrod,et al.  The fate of caffeine in man and a method for its estimation in biological material. , 1953, The Journal of pharmacology and experimental therapeutics.