Abstract
A mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) model was developed for exendin-4 to account for receptor-mediated endocytosis via glucagon-like peptide 1 receptor (GLP-1R) as the primary mechanism for its nonlinear disposition. Time profiles of exendin-4 concentrations after intravenous, subcutaneous, and continuous intravenous infusion doses in rats, intravenous and subcutaneous doses in monkeys, and intravenous infusion and subcutaneous doses in humans were examined. Mean data for glucose and insulin after glucose challenges during exendin-4 treatment in healthy rats were analyzed. The PK model components included receptor binding, subsequent internalization and degradation, nonspecific tissue distribution, and linear first-order elimination from plasma. The absorption rate constant (k(a)) decreased with increasing doses in all three species. The clearance from the central compartment (CL(c)) (rats, 3.62 ml/min; monkeys, 2.39 ml · min(-1) · kg(-1); humans, 1.48 ml · min(-1) · kg(-1)) was similar to reported renal clearances. Selected PK parameters (CL(c), V(c), and k(off)) correlated allometrically with body weight. The equilibrium dissociation constant (K(D)) was within the reported range in rats (0.74 nM), wherea...Continue Reading
References
Jan 1, 1974·Pflügers Archiv : European journal of physiology·G PopaM Steinhausen
Aug 15, 1995·The Biochemical Journal·C WidmannB Thorens
Aug 1, 1995·Neuroendocrinology·R GökeS P Sheikh
Mar 1, 1997·Neuroscience·P J LarsenC Orskov
Apr 4, 2000·Endocrinology·F SatohD M Smith
Apr 25, 2001·Metabolism: Clinical and Experimental·D G ParkesA Young
May 10, 2002·Journal of Pharmacokinetics and Pharmacodynamics·D E Mager, W J Jusko
Jun 17, 2004·The Journal of Pharmacology and Experimental Therapeutics·Donald E MagerDariush Elahi
Aug 28, 2004·Diabetes·Kristine B DegnOle Schmitz
Feb 11, 2005·American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists·Orville G KoltermanAlain D Baron
May 27, 2006·Current Drug Metabolism·Kathrin CopleyDavid G Parkes
Feb 20, 2007·Pharmacology & Therapeutics·Máire E Doyle, Josephine M Egan
Apr 13, 2007·Drugs·Risto S Cvetković, Greg L Plosker
May 4, 2007·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Meike KörnerJean Claude Reubi
Jul 6, 1923·Science·G S Adair
Jan 9, 2008·International Journal of Pharmaceutics·Guo AiYuanguo Cheng
Feb 23, 2008·International Journal of Pharmaceutics·Bronislava R GedulinAndrew A Young
Jun 11, 2008·The Journal of Histochemistry and Cytochemistry : Official Journal of the Histochemistry Society·Ditte TornehaveR Scott Heller
Jan 22, 2009·Biopharmaceutics & Drug Disposition·Jin Y Jin, William J Jusko
Mar 17, 2010·Pharmaceutical Research·Leonid KaganDonald E Mager
Dec 16, 2010·The Journal of Pharmacology and Experimental Therapeutics·Wei Gao, William J Jusko
Citations
Dec 25, 2012·Journal of Pharmacokinetics and Pharmacodynamics·Karen B SchneckVikram P Sinha
Dec 12, 2012·Pharmaceutical Research·Ting ChenLeonid Kagan
Jan 18, 2014·Drugs·Paul L McCormack
May 24, 2014·Pharmaceutical Research·Leonid KaganDonald E Mager
Dec 13, 2012·Expert Opinion on Drug Discovery·David G ParkesMichael E Trautmann
Apr 2, 2013·Advanced Drug Delivery Reviews·Eric Ezan
Sep 6, 2014·Journal of the American Chemical Society·Lisa M JohnsonSamuel H Gellman
Aug 1, 2015·CPT: Pharmacometrics & Systems Pharmacology·P DuaP H van der Graaf
Aug 2, 2014·The Journal of Surgical Research·Ioannis ChristakisStephen Bloom
Mar 3, 2015·Journal of Pharmacological Sciences·Hanqing LiXiaohong Fan
Aug 15, 2014·Frontiers in Pharmacology·Tove TuntlandKeith Hoffmaster
Mar 21, 2015·PloS One·Afaf SahraouiHanne Scholz
Oct 1, 2016·Journal of Investigative Surgery : the Official Journal of the Academy of Surgical Research·Ioannis ChristakisStephen Bloom
Oct 6, 2016·ACS Chemical Biology·Yan LiuFeng Wang
Sep 22, 2016·British Journal of Clinical Pharmacology·Brenda Cirincione, Donald E Mager
Oct 16, 2015·Journal of Lipid Research·Masato FuruhashiTetsuji Miura
Jun 24, 2017·CPT: Pharmacometrics & Systems Pharmacology·S BihorelE Ludwig
Oct 20, 2018·Journal of Clinical Pharmacology·Karen SchneckJesus Reviriego
Jul 13, 2017·The Journal of Pharmacology and Experimental Therapeutics·Shinji IwasakiNobuyuki Amano
Aug 15, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Leonid Kagan
May 22, 2020·British Journal of Pharmacology·Philip PickfordBen Jones
May 26, 2017·Journal of Clinical Pharmacology·Brenda CirincioneDonald E Mager
Oct 18, 2019·JCI Insight·Ki-Suk KimDarleen A Sandoval
Nov 22, 2019·Scientific Reports·Yazhou LiNigel H Greig
Mar 28, 2013·American Journal of Physiology. Endocrinology and Metabolism·Manuel Gil-LozanoFederico Mallo
May 5, 2017·Frontiers in Bioengineering and Biotechnology·Magnus TrägårdhPeter Gennemark
Aug 12, 2017·Biochemistry·Jens T BukrinskiPernille Harris