Biopharmaceutics

Liver

Multidisciplinary Drug Targeting and Delivery Approaches in the Postgenomic Era

The head of this research group is Professor Hans Lennernäs (his CV is given below).

The overall aim of this research program is to develop novel principles for specific drug delivery and targeting to the active site by using complex in vivo models. An innovative, cutting edge and multi-disciplinary collaboration using clinical models will include research teams from: pharmaceutical technology, material science, biopharmaceutics and pharmacokinetics, drug metabolism, toxicology, oncology, gastroenterology, endocrinology, urology and regulatory science. All four projects are based on an in-depth understanding of the clinical significance and functional activity of carrier-mediated membrane transport and intracellular enzymatic processes in the entero-hepatobiliary system, various tumour tissues and other target organs.


The current research program has four projects
  • Specific targeting to the entero-hepatobiliary system based on ADME and clinical principles
  • Novel oral formulations of poorly soluble compounds using principles from dietary lipid processing
  • Novel approaches for drug targeting of anti-cancer drugs based on ADME and clinical principles
  • Develop new drug delivery principles where it exists a clinical need (such as sublingual delivery of fentanyl to cancer patients with incident (breakthrough) pain)

In the postgenomic era it is recognized that the specific function of proteins and their complex interplay in vivo is crucial for further medical progress. We are therefore using advanced clinical research models, which are well established in our laboratory (such GI-intubation techniques, i.e. Loc-I-Gut, Loc-I-Bile-a bile sampling tube, Nyberg Capsule) to examining the complex in vivo entero-hepatobiliary physiology in humans, with focus on transit, membrane transport and metabolism. This research has the potential to establish new in vivo valid principles for delivery and targeting of drugs to this enterohepatic cycle and to develop novel formulation principles for poorly soluble drugs.

Presently, several such new anti-cancer approaches are in various stages of clinical development, providing exciting perspectives for the future of cancer cure. However one important factor for a successful outcome of such therapeutic approaches is ensuring local specific targeting of the therapeutic moiety at the tumour site.

One illustrative example of our development of new treatment principles is the successful work with a rapid release transmucosal delivery of fentanyl in incident pain. It has clearly demonstrated that there is a need and possibility to develop new delivery system (Lennernäs et al, 2004).

New and improved drug therapy In the postgenomic era a multidisciplinary collaboration with a focus on in vivo models is crucial for the successful search of novel targeting principles in various organs. (DMPK=drug metabolism&pharmacokinetics)

These four projects are based on a strong already established multidisciplinary collaboration among: bioanalytical chemistry (Prof. Ulf Bondesson,UU), gastroenterology (Dr. Lars Knutson,UU), pharmaceutics and physical chemistry (Dr. Bertil Abrahamsson, Dr. Paul Dickson,AZ,Galenica AB), clinical pharmacology and neurology (Prof. Thomas Hedner,GU), clinical oncology and urology (Dr Bo Lennernäs, GU), molecular biology and biopharmaceutics/pharmacokinetics/drug metabolism (our own group and Dr. Ulf Bredberg,AZ). My research group has 7 fully financed Ph.D students and 1 post doc working in the field. We have strong international collaboration with University of Michigan, Danish faculty of pharmaceutical science and several major international pharmaceutical companies as well as small pharmaceutical companies. (UU=Uppsala Univ, GU=Göteborg Univ, AZ=AstraZeneca)

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Curriculum vitae

Hans Lennernäs, Ph.D. Professor in Biopharmaceutics

Dr. Hans Lennernäs is a full professor of Biopharmaceutics at Uppsala University since 1 July 2000, Sweden and he also holds an adjunct professor of Biopharmaceutics at Royal Danish School of Pharmacy in Copenhagen, Denmark since 2000. His research interest is focused on clinical significance of mechanisms and regulation of membrane transport and metabolism of drugs/metabolites in the gastrointestinal tract, hepatobiliary system and cancer tissues. This work is performed in vivo with clinical models in humans and in various tissue and cell culture models. His research aims to develop novel strategies of tissue drug targeting and delivery that aims to improve the clinical use and efficacy of drugs in various disease states, such as metabolic and cancer diseases. Hans Lennernäs has together with gastroenterologists developed and validated two new clinical intestinal perfusion techniques for investigations of intestinal transport and metabolism of drugs and nutrients. He has been the Principal Investigator in an extensive collaboration with Food Drug & Administration, USA, University of Michigan, USA, and Medical Product Agency, Sweden during several years to develop a new guideline for the Biopharmaceutics Classification System. He has established an extensive human permeability database (45 compounds) that today is widely used in academia and pharmaceutical industry. He has contributed to the understanding of how drugs are transported and metabolised in the intestine and the liver in vivo in humans. Dr. Lennernäs is the chairman for the World Conference in Drug Absorption, Transport and Delivery that will be held in Barcelona in May 2005. He serves as reviewer for several scientific journals. His work had led to more 125 publications, 145 invited lectures and more than 250 submitted presentations at scientific meetings. He has supervised 12 doctorial theses and acted as co-supervisor for two neurologists. He has obtained several national and international research grants. Dr. Lennernäs has received Glaxo Wellcome Achievement Award 1997, Annual Award from the Industrial Pharmacy Section 1998, Fédération Internationale Pharmaceutique (FIP), a Honourable Mentions at EURAND AWARD 2000, been elected the AAPS Fellow 2004 and received the AAPS Meritorious Manuscript Award 2004. He is on the board of the non-profit Drug Delivery Foundation, which promotes research and education in this area all around the world. He is also one of the innovators to a novel sublingual drug delivery system for the treatment of various acute pain conditions. In total, he has invented five patent/patent applications, which have resulted in drug products in pre-clinical phase and in preparation for phase I and III clinical trials. His research team is currently composed of 7 Ph.D. students, and has an extensive national and international interdisciplinary collaboration with both universities and national and international pharmaceutical companies.

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About Us

Group members
  • Hans Lennernäs, professor.
  • Erik Sjögren, researcher.
  • Emelie Ahnfelt, doctoral student.
  • Ilse Dubbelboer, doctoral student.
  • Elsa Lilienberg, doctoral student.
  • David Dahlgren, assistant.
  • Carl Roos, assistant.
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Key References

Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokin.42, 1141-1160, 2003.

Christer Tannergren,  Niclas Petri, Lars Knutson, Mikael Hedeland Ulf Bondesson and Hans Lennernäs. Multiple transport mechanisms involved in the intestinal absorption and first pass extraction of fexofenadine. Clin. Pharmacol & Ther. 74: 423-36 (2003).

Lennernas B, Albertsson P, Lennernas H, Norrby K. Chemotherapy and antiangiogenesis--drug-specific, dose-related effects. Acta Oncol. 42: 294-303, 2003

Lennernäs H and Fager G. Clinical Pharmacokinetics and Pharmacodynamics of HMG-CoA reductase inhibitors: similarties and dissimilarties. Clin Pharmacokin. 35, 403-425 (1997).

Tannergren C, Engman H, Knutson L, Hedeland M, Bondesson U and Lennernas H. St Johns wort decreases the bioavailability of R- and S-verapamil through induction of the first-pass metabolismwhere we used our in vivo perfusion model in human subjects. Clin. Pharmacol & Ther. 75: 298-309, (2004)

Lennernäs B Hedner T, Holmberg M, Bredenberg S, Nyström C and Lennernäs H. Clinical pharmacokinetics and safety of fentanyl following sublingual administration of a rapidly dissolving tablet in cancer patients: a new approach to treatment of incident pain. Br. J. Clin. Pharmacol. (in press) 2004.

Lindahl A., Sandström R. Ungell A-L., Abrahmsson B., Knutson L., Knutson T. and Lennernäs H. Jejunal permeability and hepatic extraction of fluvastatin in humans. Clin. Pharm. and Ther. 60, 493-503 (1996).

Nyholm D., Lennernäs H., Gomes-Trolin C. and Aquilonius S-M. Levodopa pharmacokinetics and motor performance during activities of daily living in patients with Parkinson’s disease on individual drug combinations. Clin. Neuropharmacology, 25, 89-96,2002

Amidon G.L., Lennernäs H., Shah V. and Crison J. Theoretical considerations in the correlation of drug product dissolution and in vivo bioavailability: A biopharmaceutical drug classification. Pharm. Res. 12, 413-420, (1995).

Sandström R., Knutson L., Knutson T., Jansson B. and Lennernäs H. The effect of ketoconazole on jejunal permeability and CYP 3A4 metabolism of R/S-verapamil in humans. Br. J. Clin. Pharmacol. 48, 180-189, (1999).

Sun, D., Lennernäs, H., Welage, L.S., Barnett, J.L., Landowski, C.P., Foster, D., Fleisher, D., Lee, K.-D. and Amidon, G.L. Comparison of human duodenum and Caco-2 gene expression profiles for 12,000 gene sequences tags and correlation with permeability of 26 drugs.. Pharm. Res. 19, 1400-1416, 2002.

Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernäs H, Hussain AS, and Amidon GL. A Provisional Biopharmaceutic Classification of Orally Administered WHO Essential Medicines Based on Molecular Properties:  Implications for Bioequivalence Regulatory Standards. 1, 1: 85-96 (2004)

Winiwarter S., Bonham N, Hallberg A., Lennernäs H. and Karlén A. Correlation of human jejunal permeability (in vivo) with experimentally and theoretically derived parameters. A multivariate data analysis approach J. Med. Chem. 41, 4939-4949, (1999).

Petri N, Tannergren C, Rungstad D and Lennernäs H. Transport characteristics of fexofenadine in the Caco-2 cell model. Pharm Res 21:1398-404  (2004).

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