A Physiologically Based Pharmacokinetic Model of the Minipig: Data Compilation and Model Implementation

In today’s pharmaceutical research and development, physiologically-based pharmacokinetic (PBPK) modeling plays an important role in the design, evaluation and interpretation of pharmacokinetic, toxicokinetic and formulation studies. PBPK models incorporate in vitro physicochemical and biochemical data in a physiologically based model framework to simulate in vivo exposure. The comparison of simulated concentrations to those measured in in vivo studies can be used to gain insights into compound behavior and to inform PBPK based human pharmacokinetic predictions. The Göttingen minipig is gaining importance as a large animal model in pharmaceutical research due to its physiological and anatomical similarities to human and is increasingly replacing dog and non-human primate in preclinical studies. However, no PBPK model for minipig has yet been published. This review discusses the information available to establish the physiological database for this species and highlights the gaps in current knowledge. A preliminary PBPK model is created from this database and simulations for two drugs dosed both intravenously and orally are compared to measured plasma concentrations. Results support the validity of the model with simulated plasma concentrations within the range of the observations. In conclusion, the model will need to be refined as additional physiological data become available, but it can already provide useful simulations to assist pharmaceutical research and development in the minipig.

[1]  H. Simianer,et al.  Modeling the growth of the Goettingen minipig. , 2007, Journal of animal science.

[2]  R. Upton.  Organ weights and blood flows of sheep and pig for physiological pharmacokinetic modelling. , 2008, Journal of pharmacological and toxicological methods.

[3]  C. Juste,et al.  Ion-pair high-performance liquid chromatography of bile salt conjugates: Application to pig bile , 1991, Lipids.

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

[5]  X. Lei,et al.  Cecum is the major degradation site of ingested inulin in young pigs. , 2007, The Journal of nutrition.

[6]  P. Gervasi,et al.  Expression and inducibility by phenobarbital of CYP2C33, CYP2C42, CYP2C49, CYP2B22, and CYP3As in porcine liver, kidney, small intestine, and nasal tissues , 2010, Xenobiotica; the fate of foreign compounds in biological systems.

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

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

[9]  C. Parks,et al.  Systemic Distribution of Blood Flow in Swine while Awake and during 1.0 and 1.5 MAC Isoflurane Anesthesia with or without 50% Nitrous Oxide , 1983, Anesthesia and analgesia.

[10]  M. Wilhelm,et al.  Bioavailability of PCDD/F from contaminated soil in young Goettingen minipigs. , 2007, Chemosphere.

[11]  Kiyohiko Sugano,et al.  Oral Absorption of Poorly Water-Soluble Drugs: Computer Simulation of Fraction Absorbed in Humans from a Miniscale Dissolution Test , 2006, Pharmaceutical Research.

[12]  D. Cosgrove,et al.  Quantification of blood flow , 2001, European Radiology.

[13]  J. Heesterbeek,et al.  Does cardiovascular performance of modern fattening pigs obey allometric scaling laws? , 2009, Journal of animal science.

[14]  S. Nathanson,et al.  Rates of flow of technetium 99m-labeled human serum albumin from peripheral injection sites to sentinel lymph nodes , 1996, Annals of Surgical Oncology.

[15]  T. Lavé,et al.  A Novel Strategy for Physiologically Based Predictions of Human Pharmacokinetics , 2006, Clinical pharmacokinetics.

[16]  A. Flach,et al.  Morphological and functional adaptation after massive resection of the small intestine: experiments using minipigs of the Göttingen strain. , 1978, Progress in pediatric surgery.

[17]  C. Nyström,et al.  The effect of dry mixing on the apparent solubility of hydrophobic, sparingly soluble drugs. , 1999, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[18]  K. Higaki,et al.  Prediction of oral absorption of griseofulvin, a BCS class II drug, based on GITA model: utilization of a more suitable medium for in-vitro dissolution study. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[19]  H. Lennernäs,et al.  Different Effects of Ketoconazole on the Stereoselective First-Pass Metabolism of R/S-Verapamil in the Intestine and the Liver: Important for the Mechanistic Understanding of First-Pass Drug-Drug Interactions , 2009, Drug Metabolism and Disposition.

[20]  Thierry Lavé,et al.  Predicting Pharmacokinetic Food Effects Using Biorelevant Solubility Media and Physiologically Based Modelling , 2006, Clinical pharmacokinetics.

[21]  A. Bollinger,et al.  Flow velocity of single lymphatic capillaries in human skin. , 1996, The American journal of physiology.

[22]  P. Marín,et al.  Pharmacokinetics and milk penetration of moxifloxacin after intramuscular administration to lactating goats. , 2007, Veterinary journal.

[23]  O. Adeola,et al.  Developmental changes in morphometry of the small intestine and jejunal sucrase activity during the first nine weeks of postnatal growth in pigs. , 2006, Journal of animal science.

[24]  C. Ioannides.  Cytochrome p450 expression in the liver of food-producing animals. , 2006, Current drug metabolism.

[25]  R. Oberle,et al.  Variability in Gastric pH and Delayed Gastric Emptying in Yucatan Miniature Pigs , 1994, Pharmaceutical Research.

[26]  C. Kohlsdorfer,et al.  Pharmacokinetics of the 8-methoxyquinolone, moxifloxacin: a comparison in humans and other mammalian species. , 1999, The Journal of antimicrobial chemotherapy.

[27]  J. Dressman,et al.  Animal models for oral drug absorption , 1991 .

[28]  M. Dacasto,et al.  Comparative expression of liver cytochrome P450-dependent monooxygenases in the horse and in other agricultural and laboratory species. , 2003, Veterinary journal.

[29]  J Kvĕtina,et al.  Presence and activity of cytochrome P450 isoforms in minipig liver microsomes. Comparison with human liver samples. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[30]  I. Wilding,et al.  The effects of pharmaceutical excipients on small intestinal transit. , 1995, British journal of clinical pharmacology.

[31]  T. Hayden,et al.  Physiological model for distribution of sulfathiazole in swine. , 1984, Journal of pharmaceutical sciences.

[32]  Stefan Willmann,et al.  Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part II: extension to describe performance of solid dosage forms. , 2012, Journal of pharmaceutical sciences.

[33]  A. Makin,et al.  Dermal Toxicity Studies: Skin Architecture, Metabolism, Penetration and Toxicological and Pharmacological Methods , 2011 .

[34]  Shi Ke,et al.  Quantitative imaging of lymph function. , 2007, American journal of physiology. Heart and circulatory physiology.

[35]  G. Crean,et al.  Comparison of gastric body and antral pH: a 24 hour ambulatory study in healthy volunteers. , 1989, Gut.

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

[37]  G. Keusch,et al.  Effects of bile and bile salts on growth and membrane lipid uptake by Giardia lamblia. Possible implications for pathogenesis of intestinal disease. , 1985, The Journal of clinical investigation.

[38]  A. Wilfart,et al.  Digesta transit in different segments of the gastrointestinal tract of pigs as affected by insoluble fibre supplied by wheat bran , 2007, British Journal of Nutrition.

[39]  Erik C von Rosenvinge,et al.  Gastrointestinal peptides and regulation of gastric acid secretion , 2010, Current opinion in endocrinology, diabetes, and obesity.

[40]  B. Richelsen,et al.  The obese Göttingen minipig as a model of the metabolic syndrome: dietary effects on obesity, insulin sensitivity, and growth hormone profile. , 2001, Comparative medicine.

[41]  T. Friedberg,et al.  Endogenous drug transporters in in vitro and in vivo models for the prediction of drug disposition in man. , 2002, Biochemical pharmacology.

[42]  Jörg Huwyler,et al.  Combinatorial QSAR modeling of human intestinal absorption. , 2011, Molecular pharmaceutics.

[43]  Tim Morris,et al.  Physiological Parameters in Laboratory Animals and Humans , 1993, Pharmaceutical Research.

[44]  J. Dent,et al.  Pyloric motor function during emptying of a liquid meal from the stomach in the conscious pig. , 1990, The Journal of physiology.

[45]  J. Sims,et al.  The utility of the minipig as an animal model in regulatory toxicology. , 2010, Journal of pharmacological and toxicological methods.

[46]  G. Amidon,et al.  Applying the biopharmaceutics classification system to veterinary pharmaceutical products. Part II. Physiological considerations. , 2002, Advanced drug delivery reviews.

[47]  Robin Hull,et al.  A good practice guide to the administration of substances and removal of blood, including routes and volumes , 2001, Journal of applied toxicology : JAT.

[48]  H. Lennernäs,et al.  Extensive intestinal glucuronidation of raloxifene in vivo in pigs and impact for oral drug delivery , 2012, Xenobiotica; the fate of foreign compounds in biological systems.

[49]  G. Amidon,et al.  Comparison of gastrointestinal pH in dogs and humans: implications on the use of the beagle dog as a model for oral absorption in humans. , 1986, Journal of pharmaceutical sciences.

[50]  K. Wikvall,et al.  Porcine microsomal vitamin D(3) 25-hydroxylase (CYP2D25). Catalytic properties, tissue distribution, and comparison with human CYP2D6. , 2000, The Journal of biological chemistry.

[51]  W. J. van der Giessen,et al.  Effect of Epinine on Systemic Hemodynamics and Regional Blood Flow in Conscious Pigs , 1992, Journal of cardiovascular pharmacology.

[52]  T. Nabeshima,et al.  Intracutaneous Distributions of Fluconazole, Itraconazole, and Griseofulvin in Guinea Pigs and Binding to Human Stratum Corneum , 2004, Antimicrobial Agents and Chemotherapy.

[53]  G. Burckhardt,et al.  Cloning of the pig renal organic anion transporter 1 (pOAT1). , 2002, Biochimie.

[54]  J. Dressman,et al.  Dissolution Media Simulating Conditions in the Proximal Human Gastrointestinal Tract: An Update , 2008, Pharmaceutical Research.

[55]  J. A. D. Leeuw,et al.  An Animal Model to Study Digesta Passage in Different Compartments of the Gastro-Intestinal Tract (GIT) as Affected by Dietary Composition , 2006 .

[56]  N. Lehn,et al.  Tissue concentrations of vancomycin and Moxifloxacin in periprosthetic infection in rats , 2007, Acta orthopaedica.

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

[58]  J. Bülow,et al.  Reversibility of the effects on local circulation of high lipid concentrations in blood. , 1990, Scandinavian journal of clinical and laboratory investigation.

[59]  L. Ellegaard,et al.  The RETHINK project on minipigs in the toxicity testing of new medicines and chemicals: conclusions and recommendations. , 2010, Journal of pharmacological and toxicological methods.

[60]  A. Rostami-Hodjegan,et al.  Cytochrome P450 Pig Liver Pie: Determination of Individual Cytochrome P450 Isoform Contents in Microsomes from Two Pig Livers Using Liquid Chromatography in Conjunction with Mass Spectrometry , 2011, Drug Metabolism and Disposition.

[61]  G. Glenn,et al.  Transcutaneous immunization of domestic animals: opportunities and challenges. , 2000, Advanced drug delivery reviews.

[62]  C. Friis,et al.  Is cytochrome P450 CYP2D activity present in pig liver? , 2002, Pharmacology & toxicology.

[63]  P. Gervasi,et al.  Xenobiotic-metabolizing enzymes in pig nasal and hepatic tissues. , 1998, Xenobiotica; the fate of foreign compounds in biological systems.

[64]  R. Weaver,et al.  Determining the best animal model for human cytochrome P450 activities: a comparison of mouse, rat, rabbit, dog, micropig, monkey and man , 2000, Xenobiotica; the fate of foreign compounds in biological systems.

[65]  Jan Snoeys,et al.  From preclinical to human – prediction of oral absorption and drug–drug interaction potential using physiologically based pharmacokinetic (PBPK) modeling approach in an industrial setting: a workflow by using case example , 2012, Biopharmaceutics & drug disposition.

[66]  P. Souček,et al.  Model systems based on experimental animals for studies on drug metabolism in man: (mini)pig cytochromes P450 3A29 and 2E1. , 2005, Basic & clinical pharmacology & toxicology.

[67]  Stefan Willmann,et al.  An update on computational oral absorption simulation , 2011, Expert opinion on drug metabolism & toxicology.

[68]  J. Nyengaard,et al.  The association between renal function and structural parameters: a pig study , 2008, BMC nephrology.

[69]  T Kurihara-Bergstrom,et al.  Characterization of the Yucatan miniature pig skin and small intestine for pharmaceutical applications. , 1986, Laboratory animal science.

[70]  G. Burckhardt,et al.  Functional expression of pig renal organic anion transporter 3 (pOAT3). , 2005, Biochimie.

[71]  H. E. Hansen,et al.  The pharmacokinetics and acute renal effects of oral microemulsion ciclosporin A in normal pigs. , 2006, International immunopharmacology.

[72]  H. Lennernäs,et al.  The pharmacokinetics and hepatic disposition of repaglinide in pigs: mechanistic modeling of metabolism and transport. , 2012, Molecular pharmaceutics.

[73]  W. S. Snyder,et al.  Report of the task group on reference man , 1979, Annals of the ICRP.

[74]  T Lavé,et al.  Challenges and opportunities with modelling and simulation in drug discovery and drug development , 2007, Xenobiotica; the fate of foreign compounds in biological systems.

[75]  M. Stromberg,et al.  Ultrastructure of the Integument of the Domestic Pig (Sus scroh) from One through Fourteen Weeks of Age , 1985, Anatomia, histologia, embryologia.

[76]  Hannah M Jones,et al.  Simulation of Human Intravenous and Oral Pharmacokinetics of 21 Diverse Compounds Using Physiologically Based Pharmacokinetic Modelling , 2011, Clinical pharmacokinetics.

[77]  I. Reid,et al.  Effect of Intravertebral Angiotensin II on Cardiac Output and Its Distribution in Conscious Dogs , 1988, Circulation research.

[78]  M. Swindle,et al.  Swine in the laboratory: surgery, anesthesia, imaging, and experimental techniques , 2007 .

[79]  T. Singer,et al.  Minipig as a potential translatable model for monoclonal antibody pharmacokinetics after intravenous and subcutaneous administration , 2012, mAbs.

[80]  M. Hossain,et al.  Gastrointestinal Transit of Nondisintegrating, Nonerodible Oral Dosage Forms in Pigs , 1990, Pharmaceutical Research.

[81]  J. Dressman,et al.  Evolution of a detailed physiological model to simulate the gastrointestinal transit and absorption process in humans, part 1: oral solutions. , 2011, Journal of pharmaceutical sciences.

[82]  M. Schubert.  Gastric exocrine and endocrine secretion , 2009, Current opinion in gastroenterology.

[83]  A. Basit,et al.  Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development. , 2011, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[84]  Leslie Z Benet,et al.  Lead PK commentary: predicting human pharmacokinetics. , 2011, Journal of pharmaceutical sciences.

[85]  Ivan Nestorov,et al.  Whole-body physiologically based pharmacokinetic models , 2007, Expert opinion on drug metabolism & toxicology.

[86]  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.

[87]  M. Gibaldi,et al.  Solubilizing properties of bile salt solutions. II. Effect of inorganic electrolyte, lipids, and a mixed bile salt system on solubilization of glutethimide, griseofulvin, and hexestrol. , 1966, Journal of pharmaceutical sciences.

[88]  S. Amae,et al.  The expression of intestinal CYP3A4 in the piglet model. , 2004, Transplantation Proceedings.

[89]  M. Skaanild.  Porcine cytochrome P450 and metabolism. , 2006, Current pharmaceutical design.

[90]  J. Graff,et al.  Gastrointestinal mean transit times in young and middle-aged healthy subjects. , 2001, Clinical physiology.

[91]  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.

[92]  H. Yamazaki,et al.  Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. , 1994, The Journal of pharmacology and experimental therapeutics.

[93]  James H. Brown,et al.  The origin of allometric scaling laws in biology from genomes to ecosystems: towards a quantitative unifying theory of biological structure and organization , 2005, Journal of Experimental Biology.

[94]  M. Delp,et al.  Physiological Parameter Values for Physiologically Based Pharmacokinetic Models , 1997, Toxicology and industrial health.

[95]  J. Crison,et al.  A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability , 1995, Pharmaceutical Research.

[96]  M. Niemi,et al.  Membrane transporters in drug development , 2010, Nature Reviews Drug Discovery.

[97]  J. Heesterbeek,et al.  Cardiovascular performance of adult breeding sows fails to obey allometric scaling laws. , 2011, Journal of animal science.

[98]  Paul S Price,et al.  Modeling Interindividual Variation in Physiological Factors Used in PBPK Models of Humans , 2003, Critical reviews in toxicology.

[99]  Keith K. H. Chan,et al.  Pharmacokinetics and Metabolism of Diclofenac Sodium in Yucatan Miniature Pigs , 1994, Pharmaceutical Research.

[100]  F. Granderath,et al.  Ambulatory pH: monitoring with a wireless system , 2007, Surgical Endoscopy.

[101]  J E Riviere,et al.  Interspecies and interregional analysis of the comparative histologic thickness and laser Doppler blood flow measurements at five cutaneous sites in nine species. , 1990, The Journal of investigative dermatology.

[102]  Stefan Willmann,et al.  Development and Validation of a Physiology-based Model for the Prediction of Oral Absorption in Monkeys , 2007, Pharmaceutical Research.

[103]  J. Ritskes-Hoitinga,et al.  Growth differences of male and female Göttingen minipigs during ad libitum feeding: a pilot study , 2005, Laboratory animals.

[104]  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.

[105]  L. Mến,et al.  "A" molasses in diets for growing pigs. , 1990 .

[106]  J. Riviere,et al.  Development of a physiologic-based pharmacokinetic model for estimating sulfamethazine concentrations in swine and application to prediction of violative residues in edible tissues. , 2005, American journal of veterinary research.

[107]  R. Sangill,et al.  Dynamic gadolinium-enhanced MRI evaluation of porcine femoral head ischemia and reperfusion , 2003, Skeletal Radiology.

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

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

[110]  H. Lennernäs,et al.  Enterohepatic Disposition of Rosuvastatin in Pigs and the Impact of Concomitant Dosing with Cyclosporine and Gemfibrozil , 2009, Drug Metabolism and Disposition.

[111]  C. Friis,et al.  Analyses of CYP2C in porcine microsomes. , 2008, Basic & clinical pharmacology & toxicology.

[112]  F. Nakayama.  Composition of gallstone and bile: species difference. , 1969, The Journal of laboratory and clinical medicine.

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

[114]  U. Kühn.  Vergleichende anatomische Untersuchungen des Darmtraktes und des darmassoziierten lymphatischen Gewebes (GALT) bei alten Hausschweinrassen und einer modernen Fleischrasse , 2001 .

[115]  J. Kvetina,et al.  Minipig as a model for drug metabolism in man: comparison of in vitro and in vivo metabolism of propafenone. , 2003, Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia.

[116]  L. Augsburger,et al.  Applying the biopharmaceutics classification system to veterinary pharmaceutical products. Part I: biopharmaceutics and formulation considerations. , 2002, Advanced drug delivery reviews.

[117]  H. Simianer,et al.  Genetic management of the Göttingen Minipig population. , 2010, Journal of pharmacological and toxicological methods.

[118]  D. Farrell,et al.  Identification of multiple constitutive and inducible hepatic cytochrome P450 enzymes in market weight swine. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[119]  M. van Griensven,et al.  Isolation of pig bone marrow mesenchymal stem cells suitable for one‐step procedures in chondrogenic regeneration , 2010, Journal of tissue engineering and regenerative medicine.

[120]  Amin Rostami-Hodjegan,et al.  Simulation and prediction of in vivo drug metabolism in human populations from in vitro data , 2007, Nature Reviews Drug Discovery.

[121]  H. Dumon,et al.  Evaluation of association between body size and large intestinal transit time in healthy dogs. , 2006, American journal of veterinary research.

[122]  M. Rowland,et al.  Absorption kinetics of griseofulvin in man. , 1968, Journal of pharmaceutical sciences.

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

[124]  P. Gervasi,et al.  Xenobiotic metabolizing cytochrome P450 in pig, a promising animal model. , 2011, Current drug metabolism.

[125]  N. Kaniwa,et al.  Bioavailability of griseofulvin from plain tablets in Göttingen minipigs and the correlation with bioavailability in humans. , 1984, Journal of pharmacobio-dynamics.

[126]  Niels-Christian Ganderup,et al.  Safety Assessment in the Minipig—Principal Body Systems , 2011 .

[127]  A. L. Dalmose, J. J. Hvistendahl, L. H. Olsen, A. .  Surgically Induced Urologic Models in Swine , 2000, Journal of investigative surgery : the official journal of the Academy of Surgical Research.

[128]  John M. DeSesso,et al.  Contrasting the Gastrointestinal Tracts of Mammals: Factors that Influence Absorption , 2008 .

[129]  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.

[130]  C. Friis,et al.  Cytochrome P450 sex differences in minipigs and conventional pigs. , 1999, Pharmacology & toxicology.

[131]  S. Symchowicz,et al.  Absorption, distribution, metabolism, and excretion of griseofulvin in man and animals. , 1975, Drug metabolism reviews.

[132]  L. Buéno,et al.  The effect of feeding on the motility of the stomach and small intestine in the pig , 1976, British Journal of Nutrition.

[133]  H. Lennernäs,et al.  Intestinal and Hepatobiliary Transport of Ximelagatran and Its Metabolites in Pigs , 2008, Drug Metabolism And Disposition.

[134]  J. Mcrorie,et al.  Characterization of Propagating Contractions in Proximal Colon of Ambulatory Mini Pigs , 1998, Digestive Diseases and Sciences.

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

[136]  M Matsumoto,et al.  Evaluation of Yucatan micropig skin for use as an in vitro model for skin permeation study. , 1997, Biological & pharmaceutical bulletin.

[137]  K. Sirinek,et al.  The radiolabeled microsphere technique in gut blood flow measurement--current practice. , 1984, The Journal of surgical research.

[138]  M. Zollinger,et al.  Pimecrolimus: skin disposition after topical administration in minipigs in vivo and in human skin in vitro. , 2008, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[139]  J. F. Perkins.  Physiological Considerations , 1959 .

[140]  S. S. Davis,et al.  Gastrointestinal transit of dosage forms in the pig , 2001, The Journal of pharmacy and pharmacology.

[141]  S. Frokjaer,et al.  Evaluation of Göttingen minipig skin for transdermal in vitro permeation studies. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[142]  H. S. Bal,et al.  Histomorphology of the Torus pyloricus of the Domestic Pig (Sus scrof a domestica) , 1972, Zentralblatt fur Veterinarmedizin. Reihe C: Anatomie, Histologie, Embryologie.