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• W2806410344 abstract "Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [ 11 C]AM7 and [ 11 C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([ 11 C]AM7 <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M1><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle=italic>2</mml:mn></mml:math>; [ 11 C]MT107, <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M2><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle=italic>4</mml:mn></mml:math>) and after administration of cyclosporine ([ 11 C]MT107, <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M3><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn fontstyle=italic>4</mml:mn></mml:math>). The modelling revealed a significant reduction in [ 11 C]MT107 hepatobiliary clearance from <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M4><mml:mn fontstyle=italic>35.2</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle=italic>10.9</mml:mn></mml:math> to <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M5><mml:mn fontstyle=italic>17.1</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle=italic>5.6</mml:mn></mml:math> μ l/min after cyclosporine administration. The excretion profile of [ 11 C]MT107 was shifted from predominantly hepatobiliary (<mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M6><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=normal>C</mml:mi><mml:mi mathvariant=normal>L</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=normal>H</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>/<mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M7><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=normal>C</mml:mi><mml:mi mathvariant=normal>L</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=normal>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> = <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M8><mml:mn fontstyle=italic>3.8</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle=italic>3.0</mml:mn></mml:math>) to equal hepatobiliary and renal clearance (<mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M9><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=normal>C</mml:mi><mml:mi mathvariant=normal>L</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=normal>H</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math>/<mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M10><mml:mrow><mml:msub><mml:mrow><mml:mi mathvariant=normal>C</mml:mi><mml:mi mathvariant=normal>L</mml:mi></mml:mrow><mml:mrow><mml:mi mathvariant=normal>R</mml:mi></mml:mrow></mml:msub></mml:mrow></mml:math> = <mml:math xmlns:mml=http://www.w3.org/1998/Math/MathML id=M11><mml:mn fontstyle=italic>0.9</mml:mn><mml:mo>±</mml:mo><mml:mn fontstyle=italic>0.2</mml:mn></mml:math>). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics." @default.
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• W2806410344 date "2018-06-03" @default.
• W2806410344 modified "2023-09-25" @default.
• W2806410344 title "Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the<i> In Vivo</i> Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice" @default.
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• W2806410344 doi "https://doi.org/10.1155/2018/5849047" @default.
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