Advanced search
Publication Cover
Expert Opinion on Drug Discovery Volume 11, 2016 - Issue 1
Submit an article Journal homepage
1,199
Views
26
CrossRef citations to date
0
Altmetric
Reviews

Mechanistic models enable the rational use of in vitro drug-target binding kinetics for better drug effects in patients

Wilhelmus EA de WitteDivision of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
,
Yin Cheong WongDivision of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
,
Indira NederpeltDivision of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
,
Laura H HeitmanDivision of Medicinal Chemistry, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
,
Meindert DanhofDivision of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
,
Piet H van der GraafDivision of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
,
Ron AHJ GilissenA Division of Janssen Pharmaceutica N.V., Janssen Research and Development, Turnhoutseweg 30, Beerse2340, Belgium
&
Elizabeth C.M. de LangeDivision of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The NetherlandsCorrespondence[email protected]
 show all
Pages 45-63 | Published online: 20 Oct 2015

References

  • Hong Y, Gengo FM, Rainka MM, et al. Population pharmacodynamic modelling of aspirin- and ibuprofen-induced inhibition of platelet aggregation in healthy subjects. Clin Pharmacokinet. 2008;47(2):129–137.
  • Katashima M, Yamamoto K, Tokuma Y, et al. Comparative pharmacokinetic/pharmacodynamic analysis of proton pump inhibitors omeprazole, lansoprazole and pantoprazole, in humans. Eur J Drug Metab Pharmacokinet. 1998;23(1):19–26.
  • Äbelö A, Holstein B, Eriksson UG, et al. Gastric acid secretion in the dog: a mechanism-based pharmacodynamic model for histamine stimulation and irreversible inhibition by omeprazole. J Pharmacokinet Pharmacodyn. 2002;29(4):365–382.
  • Copeland RA. The dynamics of drug-target interactions: drug-target residence time and its impact on efficacy and safety. Expert Opin Drug Discov. 2010;5(4):305–310.
  • Tummino PJ, Copeland RA. Residence time of receptor−ligand complexes and its effect on biological function. Biochemistry. 2008;47(20):5481–5492.
  • Swinney DC. The role of binding kinetics in therapeutically useful drug action. Curr Opin Drug Discov Devel. 2009;12(1):31–39.
  • Kinzer-Ursem TL, Linderman JJ. Both ligand- and cell-specific parameters control ligand agonism in a kinetic model of g protein-coupled receptor signaling. PLoS Comput Biol. 2007;3(1):84–94.

* This model shows the influence of the receptor environment on agonism.

  • Leysen JE, Gomeren W. Different kinetic properties of neuroleptic receptor binding in the rat striatum and frontal cortex. Life Sci. 1978;23(5):447–452.
  • Perry DC, Mullis KB, Oie S, et al. Opiate antagonist receptor binding in vivo: evidence for a new receptor binding model. Brain Res. 1980;199(1):49–61.

* This paper is one of the few examples where diffusion-limited binding was identified in vivo.

  • Syrota A, Paillotin G, Davy JM, et al. Kinetics of in vivo binding of antagonist to muscarinic cholinergic receptor in the human heart studied by positron emission tomography. Life Sci. 1984;35(9):937–945.
  • Guo D, Xia L, Van Veldhoven JPD, et al. Binding Kinetics of ZM241385 derivatives at the human adenosine A2A receptor. ChemMedChem. 2014;9(4):752–761.
  • Schneider EV, Böttcher J, Huber R, et al. Structure-kinetic relationship study of CDK8/CycC specific compounds. Proc Natl Acad Sci USA. 2013;110(20):8081–8086.
  • Copeland RA, Pompliano DL, Meek TD. Drug-target residence time and its implications for lead optimization. Nat Rev Drug Discov. 2006;5(9):730–739.
  • Vauquelin G, Van Liefde I. Slow antagonist dissociation and long-lasting in vivo receptor protection. Trends Pharmacol Sci. 2006;27(7):356–359.
  • Dahl G, Akerud T. Pharmacokinetics and the drug-target residence time concept. Drug Discov Today. 2013;18(15–16):697–707.

* This paper demonstrates the impact of drug-target binding kinetics in a simple model of in vivo pharmacokinetics and target binding.

  • Guo D, Hillger JM, IJzerman AP, et al. Drug-target residence time: a case for G protein-coupled receptors. Med Res Rev. 2014;34(4):856–892.
  • Yin N, Pei J, Lai L. A comprehensive analysis of the influence of drug binding kinetics on drug action at molecular and systems levels. Mol Biosyst. 2013;9(6):1381–1389.
  • Vauquelin G, Bostoen S, Vanderheyden P, et al. Clozapine, atypical antipsychotics, and the benefits of fast-off D2 dopamine receptor antagonism. Naunyn Schmiedebergs Arch Pharmacol. 2012;385(4):337–372.

** This paper provides comprehensive simulations on the impact of binding kinetics on dopamine antagonism.

  • Vauquelin G. Rebinding: or why drugs may act longer in vivo than expected from their in vitro target residence time. Expert Opin Drug Discov. 2010;5(10):927–941.

* This paper explores the influence of diffusion-limited binding on the impact of drug-target binding kinetics on target occupancy.

  • Shimada S, Nakajima Y, Yamamoto K, et al. Comparative pharmacodynamics of eight calcium channel blocking agents in Japanese essential hypertensive patients. Biol Pharm Bull. 1996;19(3):430–437.

** This paper provides one of the few examples where drug-target binding kinetics have been estimated in vivo for a series of drugs for the same target.

  • Yun H-Y, Yun M-H, Kang W, et al. Pharmacokinetics and pharmacodynamics of benidipine using a slow receptor-binding model. J Clin Pharm Ther. 2005;30(6):541–547.
  • Steagall PVM, Pelligand L, Giordano T, et al. Pharmacokinetic and pharmacodynamic modelling of intravenous, intramuscular and subcutaneous buprenorphine in conscious cats. Vet Anaesth Analg. 2013;40(1):83–95.
  • Ramsey SJ, Attkins NJ, Fish R, et al. Quantitative pharmacological analysis of antagonist binding kinetics at CRF1 receptors in vitro and in vivo. Br J Pharmacol. 2011;164(3):992–1007.
  • Yassen A, Olofsen E, Dahan A, et al. Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine and fentanyl in rats : role of receptor equilibration kinetics. J Pharmacol Exp Ther. 2005;313(3):1136–1149.
  • Äbelö A, Andersson M, Holmberg AA, et al. Application of a combined effect compartment and binding model for gastric acid inhibition of AR-HO47108: a potassium competitive acid blocker, and its active metabolite AR-HO47116 in the dog. Eur J Pharm Sci. 2006;29(2):91–101.
  • Landersdorfer CB, He YL, Jusko WJ. Mechanism-based population pharmacokinetic modelling in diabetes: Vildagliptin as a tight binding inhibitor and substrate of dipeptidyl peptidase IV. Br J Clin Pharmacol. 2012;73(3):391–401.
  • Guo D, Mulder-Krieger T, IJzerman AP, et al. Functional efficacy of adenosine A2A receptor agonists is positively correlated to their receptor residence time. Br J Pharmacol. 2012;166(6):1846–1859.
  • Motulsky HJ, Mahan LC. The kinetics of competitive radioligand binding predicted mass action by the law of mass action. Mol Pharmacol. 1984;25(1):1–9.
  • Zweemer AJM, Nederpelt I, Vrieling H, et al. Multiple binding sites for small-molecule antagonists at the CC chemokine receptor 2. Mol Pharmacol. 2013;84(4):551–561.
  • Guo D, Van Dorp EJH, Mulder-Krieger T, et al. Dual-point competition association assay: a fast and high-throughput kinetic screening method for assessing ligand-receptor binding kinetics. J Biomol Screen. 2013;18(3):309–320.
  • Mathis G, Pierre N, Tardieu J Determination of association(kon) and dissociation(koff) rate constants of spiperone on the dopamine D2 receptor using the Tag-lite® platform. 2011. p. SBS 17th Annual Conference. Orlando, USA
  • Schiele F, Ayaz P, Fernández-Montalván A. A universal homogeneous assay for high-throughput determination of binding kinetics. Anal Biochem. 2015;468:42–49.
  • Nederpelt I, Schuldt V, Schiele F, et al. Characterization of 12 GnRH peptide agonists - a kinetic perspective. Br J Pharmacol. 2015; Epub ahead of print. doi: 10.1111/bph.13342.
  • Patching SG. Surface plasmon resonance spectroscopy for characterisation of membrane protein-ligand interactions and its potential for drug discovery. Biochim Biophys Acta. 2014;1838(1):43–55.
  • Rich RL, Myszka DG. Higher-throughput, label-free, real-time molecular interaction analysis. Anal Biochem. 2007;361(1):1–6.
  • Shiau AK, Massari ME, Ozbal CC. Back to basics: label-free technologies for small molecule screening. Comb Chem High Throughput Screen. 2008;11(3):231–237.
  • Gronewold TMA, Baumgartner A, Hierer J, et al. Kinetic binding analysis of aptamers targeting HIV-1 proteins by a combination of a microbalance array and mass spectrometry (MAMS). J Proteome Res. 2009;8(7):3568–3577.
  • Gronewold TMA. Surface acoustic wave sensors in the bioanalytical field: recent trends and challenges. Anal Chim Acta. 2007;603(2):119–128.
  • Kenakin T, Jenkinson S, Watson C. Determining the potency and molecular mechanism of action of insurmountable antagonists. J Pharmacol Exp Ther. 2006;319(2):710–723.
  • Vauquelin G, Fierens F, Verheijen I, et al. Insurmountable AT 1 receptor antagonism: the need for different antagonist binding states of the receptor glutamate signalling in the lung. Trends Pharmacol Sci. 2001;22(7):343–344.
  • Szczuka A, Wennerberg M, Packeu A, et al. Molecular mechanisms for the persistent bronchodilatory effect of the beta 2-adrenoceptor agonist salmeterol. Br J Pharmacol. 2009;158(1):183–194.
  • Lindström E, Von Mentzer B, Påhlman I, et al. Neurokinin 1 receptor antagonists: correlation between in vitro receptor interaction and in vivo efficacy. J Pharmacol Exp Ther. 2007;322(3):1286–1293.
  • Le MT, Pugsley MK, Vauquelin G, et al. Molecular characterisation of the interactions between olmesartan and telmisartan and the human angiotensin II AT1 receptor. Br J Pharmacol. 2007;151(7):952–962.
  • Atack JR, Wong DF, Fryer TD, et al. Benzodiazepine binding site occupancy by the novel GABAA receptor subtype-selective drug 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in rats, primates, and humans. J Pharmacol Exp Ther. 2010;332(1):17–25.
  • Laruelle M. Measuring dopamine synaptic transmission with molecular imaging and pharmacological challenges: the state of the art. Neuromethods. 2012;71:163–203.
  • Chernet E, Martin LJ, Li D, et al. Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: dopamine D2, serotonin 2A and NK-1 receptors as examples. Life Sci. 2005;78(4):340–346.
  • Barth VN. Typical and atypical antipsychotics: relationships between rat in vivo dopamine D(2) receptor occupancy assessed using LC/MS and changes in neurochemistry and catalepsy. Section Title: Mammalian Hormones. Ann Arbor, MI: ProQuest Information Learning Company;2006.
  • Need AB, McKinzie JH, Mitch CH, et al. In vivo rat brain opioid receptor binding of LY255582 assessed with a novel method using LC/MS/MS and the administration of three tracers simultaneously. Life Sci. 2007;81(17–18):1389–1396.
  • Hume SP, Gunn RN, Jones T. Pharmacological constraints associated with positron emission tomographic scanning of small laboratory animals. Eur J Nucl Med. 1998;25(2):173–176.
  • Kung M-P, Kung HF. Mass effect of injected dose in small rodent imaging by SPECT and PET. Nucl Med Biol. 2005;32(7):673–678.
  • Hume SP, Myers R, Bloomfield PM, et al. Quantitation of carbon-11-labeled raclopride in rat striatum using positron emission tomography. Synapse. 1992;12(1):47–54.
  • Tantawy MN, Jones CK, Baldwin RM, et al. [(18)F]Fallypride dopamine D2 receptor studies using delayed microPET scans and a modified Logan plot. Nucl Med Biol. 2009;36(8):931–940.
  • Lancelot S, Zimmer L. Small-animal positron emission tomography as a tool for neuropharmacology. Trends Pharmacol Sci. 2010;31(9):411–417.
  • Müller CP, Pum ME, Amato D, et al. The in vivo neurochemistry of the brain during general anesthesia. J Neurochem. 2011;119(3):419–446.
  • Schiffer WK, Mirrione MM, Biegon A, et al. Serial microPET measures of the metabolic reaction to a microdialysis probe implant. J Neurosci Methods. 2006;155(2):272–284.
  • Ginovart N, Sun W, Wilson AA, et al. Quantitative validation of an intracerebral beta-sensitive microprobe system to determine in vivo drug-induced receptor occupancy using [11C]Raclopride in rats. Synapse. 2004;52(2):89–99.
  • Balasse L, Maerk J, Pain F, et al. PIXSIC, a pixelated β(+)-sensitive probe for radiopharmacological investigations in rat brain: binding studies with [(18)F]MPPF. Mol Imaging Biol. 2015;17(2):163–167.
  • Polikov VS, Tresco PA, Reichert WM. Response of brain tissue to chronically implanted neural electrodes. J Neurosci Methods. 2005;148(1):1–18.
  • Wang Y, Michael AC. Microdialysis probes alter presynaptic regulation of dopamine terminals in rat striatum. J Neurosci Methods. 2012;208(1):34–39.
  • Märk J, Benoit D, Balasse L, et al. A wireless beta-microprobe based on pixelated silicon for in vivo brain studies in freely moving rats. Phys Med Biol. 2013;58(13):4483–4500.
  • Li J, Fish RL, Cook SM, et al. Comparison of in vivo and ex vivo [3H]flumazenil binding assays to determine occupancy at the benzodiazepine binding site of rat brain GABAA receptors. Neuropharmacology. 2006;51(1):168–172.
  • Schotte A, Janssen PF, Gommeren W, et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl). 1996;124(1–2):57–73.
  • Lengyel K, Pieschl R, Strong T, et al. Ex vivo assessment of binding site occupancy of monoamine reuptake inhibitors: methodology and biological significance. Neuropharmacology. 2008;55(1):63–70.
  • Langlois X, Te Riele P, Wintmolders C, et al. Use of the beta-imager for rapid ex vivo autoradiography exemplified with central nervous system penetrating neurokinin 3 antagonists. J Pharmacol Exp Ther. 2001;299(2):712–717.
  • Baker JG, Hall IP, Hill SJ. Pharmacological characterization of CGP 12177 at the human beta(2)-adrenoceptor. Br J Pharmacol. 2002;137(3):400–408.
  • Delforge J, Syrota A, Lançon JP, et al. Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical method. J Nucl Med. 1991;32(4):739–748.
  • Kessler RM, Votaw JR, Schmidt DE, et al. High affinity dopamine D2 receptor radioligands. 3.[123I] and [125I]epidepride: in vivo studies in rhesus monkey brain and comparison with in vitro pharmacokinetics in rat brain. Life Sci. 1993;53(3):241–250.
  • Mukherjee J, Yang ZY, Brown T, et al. 18F-desmethoxyfallypride: a fluorine-18 labeled radiotracer with properties similar to carbon-11 raclopride for PET imaging studies of dopamine D2 receptors. Life Sci. 1996;59(8):669–678.
  • Mukherjee J, Yang Z-Y, Lew R, et al. Evaluation of d -Amphetamine effects on the binding of dopamine D-2 receptor radioligand, 18F-fallypride in nonhuman primates using positron emission tomography. Synapse. 1997;27(1):1–13.
  • Christian BT, Narayanan T, Shi B, et al. Measuring the in vivo binding parameters of [18F]-fallypride in monkeys using a PET multiple-injection protocol. J Cereb Blood Flow Metab. 2004;24(3):309–322.
  • Vandehey NT, Moirano JM, Converse AK, et al. High-affinity dopamine D2/D3 PET radioligands 18F-fallypride and 11C-FLB457: a comparison of kinetics in extrastriatal regions using a multiple-injection protocol. J Cereb Blood Flow Metab. 2010;30(5):994–1007.
  • Leysen JE, Gommeren W. Drug-receptor dissociation time, new tool for drug research: receptor binding affinity and drug-receptor dissociation profiles of serotonin-S2, dopamine-D2, histamine-HI antagonists, and opiates. Drug Dev Res. 1986;131:119–131.
  • Perlmutter JS, Kilbourn MR, Welch MJ, et al. Non-steady-state measurement of in vivo receptor binding with positron emission tomography :“Dose Response” analysis. J Neurosci. 1989;9(7):2344–2352.
  • Leslie CA, Bennett JP. [3H]spiperone binds selectively to rat striatal D2 dopamine receptors in vivo: a kinetic and pharmacological analysis. Brain Res. 1987;407(2):253–262.
  • Kapur S, Seeman P. Antipsychotic agents differ in how fast they come off the dopamine D2 receptors. Implications for atypical antipsychotic action. J Psychiatry Neurosci. 2000;25(2):161–166.
  • Johnson M, Kozielska M, Pilla Reddy V, et al. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the dopamine D2 receptor occupancy of olanzapine in rats. Pharm Res. 2011;28(10):2490–2504.
  • Laruelle M, Abi-Dargham A, Ai-Tikriti MS, et al. SPECT quantification of [123I] lomazenil binding to benzodiazepine receptors in nonhuman primates : II. Equilibrium analysis of constant infusion experiments and correlation with in vitro parameters. J Cereb Blood Flow Metab. 1994;14(3):453–465.
  • Millet P, Graf C, Moulin M, et al. SPECT quantification of benzodiazepine receptor concentration using a dual-ligand approach. J Nucl Med. 2006;47(5):783–792.
  • Sakiyama Y, Saito M, Inoue O. Acute treatment with pentobarbital alters the kinetics of in vivo receptor binding in the mouse brain. Nucl Med Biol. 2006;33(4):535–541.
  • Sihver W, Sihver S, Bergström M, et al. Aspects for in vitro characterization of receptor ligands: receptor binding using 11C-labeled A detailed study with the benzodiazepine receptor antagonist [11C] Ro 15-1788. Nucl Med Biol. 1997;24(8):723–731.
  • Koeppe RA, Holthoff VA, Frey KA, et al. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab. 1991;11(5):735–744.
  • Ishii A, Toyama J. Binding properties of (±)[3H] benidipine hydrochloride to rat heart membranes. J Cardiovasc Pharmacol. 1993;21(2):191–196.
  • Cassel JA, Daubert JD, DeHaven RN. [(3)H]Alvimopan binding to the mu opioid receptor: comparative binding kinetics of opioid antagonists. Eur J Pharmacol. 2005;520(1–3):29–36.
  • Yassen A, Olofsen E, Romberg R, et al. Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther. 2007;81(1):50–58.
  • Yassen A, Kan J, Olofsen E, et al.. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the respiratory-depressant effect of buprenorphine and fentanyl in rats. J Pharmacol Exp Ther. 2006;319(2):682–692.
  • Casadó V, Allende G, Mallol J, et al. Thermodynamic analysis of agonist and antagonist binding to membrane-bound and solubilized A1 adenosine receptors. J Pharmacol Exp Ther. 1993;266(3):1463–1474.
  • Langlois X, Megens A, Lavreysen H, et al. Pharmacology of JNJ-37822681, a specific and fast-dissociating D2 antagonist for the treatment of schizophrenia. J Pharmacol Exp Ther. 2012;342(1):91–105.
  • Treherne JM, Young JM. Temperature-dependence of the kinetics of the binding the histamine H1 -receptor: comparison with the kinetics of [3H] -mepyramine. Br J Pharmacol. 1988;94(3):811–822.
  • Wallace RM, Young JM. Temperature dependence related compounds of the binding of [3H]Mepyramine to the Histamine H1 Receptor. Mol Pharmacol. 1983;23(1):60–66.
  • Sakai S. Effect of hormones on dissociation of prolactin from the rabbit mammary gland prolactin receptor. Biochem J. 1991;279:461–465.
  • Endres CJ, Kolachana BS, Saunders RC, et al. Kinetic modeling of [11C]raclopride: combined PET-microdialysis studies. J Cereb Blood Flow Metab. 1997;17(9):932–942.
  • Morris ED, Yoder KK. Positron emission tomography displacement sensitivity: predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics. J Cereb Blood Flow Metab. 2007;27(3):606–617.
  • Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry. 2001;158(3):360–369.
  • Wiley HS. Anomalous binding of epidermal growth factor to A431 cells is due to the effect of high receptor densities and a saturable endocytic system. J Cell Biol. 1988;107(2):801–810.
  • Packeu A, Wennerberg M, Balendran A, et al. Estimation of the dissociation rate of unlabelled ligand-receptor complexes by a “two-step” competition binding approach. Br J Pharmacol. 2010;161(6):1311–1328.
  • Vauquelin G, Van Liefde I. Radioligand dissociation measurements: potential interference of rebinding and allosteric mechanisms and physiological relevance of the biological model systems. Expert Opin Drug Discov. 2012;7(7):583–595.
  • Vauquelin G, Charlton SJ. Long-lasting target binding and rebinding as mechanisms to prolong in vivo drug action. Br J Pharmacol. 2010;161(3):488–508.
  • Peletier LA, Benson N. van der Graaf PH. Impact of protein binding on receptor occupancy: a two-compartment model. J Theor Biol. 2010;265(4):657–671.

* This paper provides insight into the possible impact of non-specific binding on target occupancy.

  • Proost JH, Wierda JM, Meijer DK. An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs. J Pharmacokinet Biopharm. 1996;24(1):45–77.
  • Kim KM, Valenzano KJ, Robinson SR, et al. Differential regulation of the dopamine D2 and D3 receptors by G protein-coupled receptor kinases and beta-arrestins. J Biol Chem. 2001;276(40):37409–37414.
  • Macey TA, Gurevich VV, Neve KA. Preferential interaction between the dopamine D2 receptor and arrestin2 in neostriatal neurons. Mol Pharmacol. 2004;66(6):1635–1642.
  • Paspalas CD, Rakic P, Goldman-Rakic PS. Internalization of D2 dopamine receptors is clathrin-dependent and select to dendro-axonic appositions in primate prefrontal cortex. Eur J Neurosci. 2006;24(5):1395–1403.
  • Dang VC, Christie MJ. Mechanisms of rapid opioid receptor desensitization, resensitization and tolerance in brain neurons. Br J Pharmacol. 2012;165(6):1704–1716.
  • Skinbjerg M, Liow J-S, Seneca N, et al. D2 dopamine receptor internalization prolongs the decrease of radioligand binding after amphetamine: a PET study in a receptor internalization-deficient mouse model. Neuroimage. 2010;50(4):1402–1407.
  • Haraguchi K, Ito K, Kotaki H, et al. Prediction of drug-induced catalepsy based on dopamine D1, D2, and muscarinic acetylcholine receptor occupancies. Drug Metab Dispos. 1997;25(6):675–684.
  • Mager DE, Jusko WJ. General pharmacokinetic model for drugs exhibiting target-mediated drug disposition. J Pharmacokinet Pharmacodyn. 2001;28(6):507–532.
  • Eppler SM, Combs DL, Henry TD, et al. A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans. Clin Pharmacol Ther. 2002;72(1):20–32.
  • Jin F, Krzyzanski W. Pharmacokinetic model of target-mediated disposition of thrombopoietin. Aaps J. 2004;6(1):86–93.
  • Retlich S, Duval V, Graefe-Mody U, et al. Impact of target-mediated drug disposition on Linagliptin pharmacokinetics and DPP-4 inhibition in type 2 diabetic patients. J Clin Pharmacol. 2010;50(8):873–885.
  • Aston PJ, Derks G, Raji A, et al. Mathematical analysis of the pharmacokinetic-pharmacodynamic (PKPD) behaviour of monoclonal antibodies: predicting in vivo potency. J Theor Biol. 2011;281(1):113–121.
  • Zhang L, Sinha V, Forgue ST, et al. Model-based drug development: the road to quantitative pharmacology. J Pharmacokinet Pharmacodyn. 2006;33(3):369–393.
  • Stone JA, Banfield C, Pfister M, et al. Model-based drug development survey finds pharmacometrics impacting decision making in the pharmaceutical industry. J Clin Pharmacol. 2010;50(S9):20S– 30S.
  • Van Der Graaf PH, Gabrielsson J. Pharmacokinetic – pharmacodynamic reasoning in drug discovery and early development. Future Med Chem. 2009;1(8):1371–1374.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Order Reprints Request Corporate Permissions

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

Request Academic Permissions

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.