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The pharmacokinetics and hepatic disposition of repaglinide in pigs: mechanistic modeling of metabolism and transport
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Biofarmaci)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. (Biofarmaci)
2012 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, Vol. 9, no 4, 823-841 p.Article in journal (Refereed) Published
Abstract [en]

The predictive power of using in vitro systems in combination with physiologically based pharmacolcinetic (PBPK) modeling to elucidate the relative importance of metabolism and carrier-mediated transport for the pharmacokinetics was evaluated using repaglinide as a model compound and pig as the test system. Repaglinide was chosen as model drug as previous studies in humans have shown that repaglinide is subject to both carrier-mediated influx to the liver cells and extensive hepatic metabolism. A multiple sampling site model in pig was chosen since it provides detailed in vivo information about the liver disposition. The underlying assumption was that both metabolism and carrier-mediated transport are also important for the hepatic disposition of repaglinide in pigs. Microsomes and primary hepatocytes were used for in vitro evaluation of enzyme kinetics and cellular disposition, respectively. In vitro data were generated both with and without metabolism inhibitors (ketoconazole, bezafibrate and trimethoprim) and transport inhibitors (diclofenac and quinine) providing input into a semi-PBPK model. In vivo data were also generated with and without the same enzyme and transporter inhibitors, alone and in combination. The pigs were given repaglinide as intravenous infusions with and without inhibitors in a sequential manner, i.e., a control phase and a test phase. Parameters describing the passive and carrier-mediated flux as well as metabolism were estimated in the control phase. The result from test phase was used to gain further knowledge of the findings from the control phase. The in vivo pig model enabled simultaneous sampling from plasma (pre- and postliver and peripheral) as well as from bile and urine. A semi-PBPK model consisting of 11 compartments (6 tissues + 5 sampling sites) was constructed for the mechanistic elucidation of the liver disposition, in vitro based in vivo predictions, sensitivity analyses and estimations of individual pharmacolcinetic parameters. Both in vitro and in vivo results showed that carrier-mediated influx was important for the liver disposition. The in vivo findings were supported by the result from the test phase where hepatic clearance (4.3 mL min(-1) kg(-1)) was decreased by 29% (metabolism inhibition), 43% (transport inhibition) and 57% (metabolism + transport inhibition). These effects were in good agreement with predicted levels. This study suggests that both metabolism and carrier-mediated uptake are of significant importance for the liver disposition of repaglinide in pigs.

Place, publisher, year, edition, pages
2012. Vol. 9, no 4, 823-841 p.
Keyword [en]
PBPK, mechanistic modelling, pharmacokinetics, hepatic disposition, repaglinide
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-132346DOI: 10.1021/mp200218pISI: 000302186700014OAI: oai:DiVA.org:uu-132346DiVA: diva2:358312
Available from: 2010-10-21 Created: 2010-10-18 Last updated: 2012-05-09Bibliographically approved
In thesis
1. Hepatic Disposition of Drugs and the Utility of Mechanistic Modelling and Simulation
Open this publication in new window or tab >>Hepatic Disposition of Drugs and the Utility of Mechanistic Modelling and Simulation
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The elimination of drugs from the body is in many cases performed by the liver. Much could be gained if an accurate prediction of this process could be made early in the development of new drugs. However, for the elimination to occur, the drug molecule needs first to get inside the liver cell.

Disposition is the expression used to encapsulate both elimination and distribution. This thesis presents novel approaches and models based on simple in vitro systems for the investigation of processes involved in the hepatic drug disposition.

An approach to the estimation of enzyme kinetics based on substrate depletion data from cell fractions was thoroughly evaluated through experiments and simulations. The results that it provided were confirmed to be accurate and robust. In addition, a new experimental setup suitable for a screening environment, i.e., for a reduced number of samples, was generated through optimal experimental design. The optimization suggested that sampling at late time points over a wide range of concentration was the most advantageous.

A model, based on data from primary hepatocytes in suspension, for the investigation of cellular disposition of metabolized drugs was developed. Information on the relative importance of metabolism and membrane protein related distribution was obtained by analysis of changes in the kinetics by specific inhibition of the various processes. The model was evaluated by comparing the results to those obtained from an in vivo study analyzed with an especially constructed mechanistic PBPK model. These investigations showed that the suggested model produced good predictions of the relative importance of metabolism and carrier mediated membrane transport for hepatic disposition.

In conclusion, new approaches for the investigation of processes involved in hepatic disposition were developed. These methods were shown to be robust and increased the output of information from already commonly implemented in vitro systems.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 72 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 132
Hepatic disposition, pharmacokinetics, mechanistic modelling, drug-drug interactions, enzyme kinetics, Vmax, Km, CLint, carrier-mediated transport, active transport, modelling, in vitro-in vivo extrapolation, physiologically based pharmacokinetic model, optimal experimental design, experimental optimization, data analysis optimization
National Category
Pharmaceutical Sciences Pharmaceutical Sciences
Research subject
urn:nbn:se:uu:diva-132571 (URN)978-91-554-7934-3 (ISBN)
Public defence
2010-12-10, B:21, Uppsala Biomedicinska Centrum - BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2010-11-18 Created: 2010-10-21 Last updated: 2011-01-13Bibliographically approved

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