Skip to main content
Log in

Impact of physiochemical properties on pharmacokinetics of protein therapeutics

  • Review
  • Published:
European Journal of Drug Metabolism and Pharmacokinetics Aims and scope Submit manuscript

Abstract

Physicochemical properties, such as molecular weight, size, partition coefficient, acid dissociation constant and solubility have a great impact on pharmacokinetics of traditional small molecule drugs and substantially used in development of small drugs. However, predicting pharmacokinetic fate (absorption, distribution, metabolism and elimination) of protein therapeutics from their physicochemical parameters is extremely difficult due to the macromolecular nature of therapeutic proteins and peptides. Their structural complexity and immunogenicity are other contributing factors that determine their biological fate. Therefore, to develop generalized strategies concerning development of therapeutic proteins and peptides are highly challenging. However, reviewing the literature, authors found that physiochemical properties, such as molecular weight, charge and structural modification are having great impact on pharmacokinetics of protein therapeutics and an attempt is made to provide the major findings in this manuscript. This manuscript will serve to provide some bases for developing protein therapeutics with desired pharmacokinetic profile.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Aggarwal S (2010) What’s fueling the biotech engine—2009–2010. Nat Biotechnol 28(11):1165

    PubMed  CAS  Google Scholar 

  • Akizawa H, Arano Y, Mifune M, Iwado A, Saito Y, Mukai T, Uehara T, Ono M, Fujioka Y, Ogawa K (2001) Effect of molecular charges on renal uptake of 111In-DTPA-conjugated peptides. Nucl Med Biol 28(7):761–768

    PubMed  CAS  Google Scholar 

  • Arend W, Silverblatt F (1975) Serum disappearance and catabolism of homologous immunoglobulin fragments in rats. Clin Exp Immunol 22(3):502

    PubMed  CAS  Google Scholar 

  • Balan V, Nelson DR, Sulkowski MS, Everson GT, Lambiase LR, Wiesner RH, Dickson RC, Post AB, Redfield RR, Davis GL (2006) A phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy. Antivir Ther 11(1):35

    PubMed  CAS  Google Scholar 

  • Banerjee PS, Hosny EA, Robinson JR (1991) Parenteral delivery of peptide and protein drugs. In: Lee VHL (ed) Peptide and protein drug delivery. Marcel Dekker, New York, pp 487–543

    Google Scholar 

  • Bansal R, Post E, Proost JH, Jager-Krikken AD, Poelstra K, Prakash J (2011) PEGylation improves pharmacokinetic profile, liver uptake and efficacy of Interferon gamma in liver fibrosis. J Control Release 154(3):233–240

    PubMed  CAS  Google Scholar 

  • Baumann A (2006) Early development of therapeutic biologics–pharmacokinetics. Curr Drug Metab 7(1):15–21

    PubMed  CAS  Google Scholar 

  • Behr TM, Sharkey RM, Sgouros G, Blumenthal RD, Dunn RM, Kolbert K, Griffiths GL, Siegel JA, Becker WS, Becker WS, Goldenberg DM, Goldenberg DM, Goldenberg DM (1997) Overcoming the nephrotoxicity of radiometal‐labeled immunoconjugates. Cancer 80(S12):2591–2610

    PubMed  CAS  Google Scholar 

  • Betz SF (1993) Disulfide bonds and the stability of globular proteins. Protein Sci 2(10):1551–1558

    PubMed  CAS  Google Scholar 

  • Bilsky EJ, Egleton RD, Mitchell SA, Palian MM, Davis P, Huber JD, Jones H, Yamamura HI, Janders J, Davis TP (2000) Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability. J Med Chem 43(13):2586–2590

    PubMed  CAS  Google Scholar 

  • Biron E, Chatterjee J, Ovadia O, Langenegger D, Brueggen J, Hoyer D, Schmid HA, Jelinek R, Gilon C, Hoffman A (2008) Improving oral bioavailability of peptides by multiple N-methylation: somatostatin analogues. Angew Chem Int Ed 47(14):2595–2599

    CAS  Google Scholar 

  • Bitonti AJ, Dumont JA, Low SC, Peters RT, Kropp KE, Palombella VJ, Stattel JM, Lu Y, Tan CA, Song JJ (2004) Pulmonary delivery of an erythropoietin Fc fusion protein in non-human primates through an immunoglobulin transport pathway. Proc Natl Acad Sci USA 101(26):9763–9768

    PubMed  CAS  Google Scholar 

  • Boswell CA, Tesar DB, Mukhyala K, Theil FP, Fielder PJ, Khawli LA (2010) Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjug Chem 21:2153–2163

    PubMed  CAS  Google Scholar 

  • Breton J, Pezzi N, Molinari A, Bonomini L, Lansen J, Buitrago GG, Prieto I (1995) Prolonged half-life in the circulation of a chemical conjugate between a pro-urokinase derivative and human serum albumin. Eur J Biochem 231(3):563–569

    PubMed  CAS  Google Scholar 

  • Byrn SR, Xu W, Newman AW (2001) Chemical reactivity in solid-state pharmaceuticals: formulation implications. Adv Drug Deliv Rev 48(1):115–136

    PubMed  CAS  Google Scholar 

  • Chatterjee J, Gilon C, Hoffman A, Kessler H (2008) N-methylation of peptides: a new perspective in medicinal chemistry. Acc Chem Res 41(10):1331–1342

    PubMed  CAS  Google Scholar 

  • Chen X, Varki A (2010) Advances in the biology and chemistry of sialic acids. ACS Chem Biol 5(2):163–176

    PubMed  CAS  Google Scholar 

  • Clarkson SB, Kimberly RP, Valinsky J, Witmer M, Bussel J, Nachman R, Unkeless J (1986) Blockade of clearance of immune complexes by an anti-F (cγ) receptor monoclonal antibody. J Exp Med 164(2):474

    PubMed  CAS  Google Scholar 

  • Constantinou A, Epenetos A, Hreczuk-Hirst D, Jain S, Wright M, Chester K, Deonarain M (2009) Site-specific polysialylation of an antitumor single-chain Fv fragment. Bioconjug Chem 20(5):924–931

    PubMed  CAS  Google Scholar 

  • Darby N, Creighton TE (1995) Disulfide bonds in protein folding and stability. Methods Mol Biol 40:219–252. doi:10.1385/0-89603-301-5:219 (Clifton, NJ)

    PubMed  CAS  Google Scholar 

  • Datta-Mannan A, Witcher DR, Tang Y, Watkins J, Wroblewski VJ (2007) Monoclonal antibody clearance. J Biol Chem 282(3):1709–1717

    PubMed  CAS  Google Scholar 

  • DeFrees S, Wang ZG, Xing R, Scott AE, Wang J, Zopf D, Gouty DL, Sjoberg ER, Panneerselvam K, Brinkman-Van der Linden ECM (2006) GlycoPEGylation of recombinant therapeutic proteins produced in Escherichia coli. Glycobiology 16(9):833–843

    PubMed  CAS  Google Scholar 

  • Dong JQ, Salinger DH, Endres CJ, Gibbs JP, Hsu CP, Stouch BJ, Hurh E, Gibbs MA (2011) Quantitative prediction of human pharmacokinetics for monoclonal antibodies: retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet 50:131–142

    PubMed  CAS  Google Scholar 

  • Durocher Y, Butler M (2009) Expression systems for therapeutic glycoprotein production. Curr Opin Biotechnol 20(6):700–707

    PubMed  CAS  Google Scholar 

  • Dutta A, Furr B, Giles M, Morley J (1976) Synthesis and biological activity of alpha-azapeptides: alpha-aza-analogues of luteinizing hormone releasing hormone. Clin Endocrinol 5:s291–s298

    Google Scholar 

  • Duttaroy A, Kanakaraj P, Osborn BL, Schneider H, Pickeral OK, Chen C, Zhang G, Kaithamana S, Singh M, Schulingkamp R, Crossan D, Bock J, Kaufman TE, Reavey P, Carey-Barber M, Krishnan SR, Garcia A, Murphy K, Siskind JK, McLean MA, Cheng S, Ruben S, Birse CE, Blondel O (2005) Development of a long-acting insulin analog using albumin fusion technology. Diabetes 54(1):251–258

    PubMed  CAS  Google Scholar 

  • Egleton R, Mitchell S, Huber J, Palian M, Polt R, Davis T (2001) Improved blood–brain barrier penetration and enhanced analgesia of an opioid peptide by glycosylation. J Pharmacol Exp Ther 299(3):967–972

    PubMed  CAS  Google Scholar 

  • Fares F, Ganem S, Hajouj T, Agai E (2007) Development of a long-acting erythropoietin by fusing the carboxyl-terminal peptide of human chorionic gonadotropin beta-subunit to the coding sequence of human erythropoietin. Endocrinology 148(10):5081–5087. doi:10.1210/en.2007-0026

    PubMed  CAS  Google Scholar 

  • Fishburn CS (2008) The pharmacology of PEGylation: balancing PD with PK to generate novel therapeutics. J Pharm Sci 97(10):4167–4183

    PubMed  CAS  Google Scholar 

  • Fracasso PM, Burris H III, Arquette MA, Govindan R, Gao F, Wright LP, Goodner SA, Greco FA, Jones SF, Willcut N (2007) A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab: pharmacokinetic and pharmacodynamic rationale for dosing. Clin Cancer Res 13(3):986–993

    PubMed  CAS  Google Scholar 

  • Geary RS (2009) Antisense oligonucleotide pharmacokinetics and metabolism. Expert Opin Drug Metab Toxicol 5(4):381–391

    PubMed  CAS  Google Scholar 

  • Ghetie V, Ward ES (2000) Multiple roles for the major histocompatibility complex class I-related receptor FcRn. Annu Rev Immunol 18(1):739–766

    PubMed  CAS  Google Scholar 

  • Gilon C, Halle D, Chorev M, Selincer Z, Byk G (1991) Backbone cyclization: a new method for conferring conformational constraint on peptides. Biopolymers 31(6):745–750

    PubMed  CAS  Google Scholar 

  • Gregoriadis G, Fernandes A, Mital M, McCormack B (2000) Polysialic acids: potential in improving the stability and pharmacokinetics of proteins and other therapeutics. Cell Mol Life Sci 57(13):1964–1969

    PubMed  CAS  Google Scholar 

  • Gregoriadis G, Jain S, Papaioannou I, Laing P (2005) Improving the therapeutic efficacy of peptides and proteins: a role for polysialic acids. Int J Pharm 300(1):125–130

    PubMed  CAS  Google Scholar 

  • Harris JM, Chess RB (2003) Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2(3):214–221

    PubMed  CAS  Google Scholar 

  • Hashida M, Mahato RI, Kawabata K, Miyao T, Nishikawa M, Takakura Y (1996) Pharmacokinetics and targeted delivery of proteins and genes. J Control Release 41(1):91–97

    CAS  Google Scholar 

  • Hashimoto T, Nomoto M, Komatsu K, Haga M, Hayashi M (2000) Improvement of intestinal absorption of peptides: adsorption of B1-Phe monoglucosylated insulin to rat intestinal brushborder membrane vesicles. Eur J Pharm Biopharm 50(2):197–204

    PubMed  CAS  Google Scholar 

  • Higgins E (2010) Carbohydrate analysis throughout the development of a protein therapeutic. Glycoconj J 27(2):211–225

    PubMed  CAS  Google Scholar 

  • Hong R, Han G, Fernández JM, Kim B, Forbes NS, Rotello VM (2006) Glutathione-mediated delivery and release using monolayer protected nanoparticle carriers. J Am Chem Soc 128(4):1078–1079

    PubMed  CAS  Google Scholar 

  • Hossler P, Mulukutla BC, Hu WS (2007) Systems analysis of N-glycan processing in mammalian cells. PLoS One 2(8):e713

    PubMed  Google Scholar 

  • Johnson CM, Oliveberg M, Clarke J, Fersht AR (1997) Thermodynamics of denaturation of mutants of barnase with disulfide crosslinks. J Mol Biol 268(1):198–208

    PubMed  CAS  Google Scholar 

  • Jong M, Breeman WAP, Bernard BF, Rolleman EJ, Hoflande LJ, Visser TJ, Setyono-Han B, Bakker WH, Pluijm ME, Krenning EP (1995) Evaluation in vitro and in rats of 161Tb-DTPA-octreotide, a somatostatin analogue with potential for intraoperative scanning and radiotherapy. Eur J Nucl Med 22(7):608–616

    PubMed  Google Scholar 

  • Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH (2010) Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet 49(8):493–507

    PubMed  CAS  Google Scholar 

  • Kobayashi H, Yoo TM, Kim IS, Kim MK, Le N, Webber KO, Pastan I, Paik CH, Eckelman WC, Carrasquillo JA (1996) l-lysine effectively blocks renal uptake of 125I-or 99mTc-labeled anti-Tac disulfide-stabilized Fv fragment. Cancer Res 56(16):3788

    PubMed  CAS  Google Scholar 

  • Kobayashi H, Kim IS, Drumm D, Kim MK, Paik DS, Le N, Waldmann TA, Carrasquillo JA, Paik CH (1999) Favorable effects of glycolate conjugation on the biodistribution of humanized antiTac Fab fragment. J Nucl Med 40(5):837–845

    PubMed  CAS  Google Scholar 

  • Kompella UB, Lee VHL (1991) Pharmacokinetics of peptide and protein drugs. Marcel Dekker, New York

    Google Scholar 

  • LaRusso NF (1984) Proteins in bile: how they get there and what they do. Am J Physiol 247(3):G199–G205

    PubMed  CAS  Google Scholar 

  • Li C, McCarthy JB, Furcht LT, Fields GB (1997) An all-D amino acid peptide model of alpha1(IV)531–543 from type IV collagen binds the alpha3beta1 integrin and mediates tumor cell adhesion, spreading, and motility. Biochemistry 36(49):15404–15410. doi:10.1021/bi971817g

    PubMed  CAS  Google Scholar 

  • Li Y, Zheng X, Tang L, Xu W, Gong M (2011) GLP-1 analogs containing disulfide bond exhibited prolonged half-life in vivo than GLP-1. Peptides 32(6):1303–1312. doi:10.1016/j.peptides.2011.04.001

    PubMed  CAS  Google Scholar 

  • Lichtenstein GR, Panaccione R, Mallarkey G (2008) Review: efficacy and safety of adalimumab in Crohn’s disease. Therap Adv Gastroenterol 1(1):43–50

    PubMed  Google Scholar 

  • Lisowska E (2002) The role of glycosylation in protein antigenic properties. Cell Mol Life Sci 59(3):445–455

    PubMed  CAS  Google Scholar 

  • Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D (1979) Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review. Kidney Int 16:251–270

    PubMed  CAS  Google Scholar 

  • Mahmood I, Green MD (2005) Pharmacokinetic and pharmacodynamic considerations in the development of therapeutic proteins. Clin Pharmacokinet 44(4):331–347

    PubMed  CAS  Google Scholar 

  • Mannaerts B, Geurts T, Odink J (1998) A randomized three-way cross-over study in healthy pituitary-suppressed women to compare the bioavailability of human chorionic gonadotrophin (Pregnyl) after intramuscular and subcutaneous administration. Hum Reprod 13(6):1461–1464

    PubMed  CAS  Google Scholar 

  • Marinaro JA, Neumann GM, Russo VC, Leeding KS, Bach LA (2000) O-glycosylation of insulin-like growth factor (IGF) binding protein-6 maintains high IGF-II binding affinity by decreasing binding to glycosaminoglycans and susceptibility to proteolysis. Eur J Biochem 267(17):5378–5386

    PubMed  CAS  Google Scholar 

  • Martinez MN, Amidon GL (2002) A mechanistic approach to understanding the factors affecting drug absorption: a review of fundamentals. J Clin Pharmacol 42(6):620–643

    PubMed  CAS  Google Scholar 

  • Matsumura M, Matthews BW (1991) Stabilization of functional proteins by introduction of multiple disulfide bonds. Methods Enzymol 202:336–356

    PubMed  CAS  Google Scholar 

  • Medzihradszky KF (2005) Characterization of protein N-glycosylation. Methods Enzymol 405:116–138

    PubMed  CAS  Google Scholar 

  • Mogensen C, Sølling K (1977) Studies on renal tubular protein reabsorption: partial and near complete inhibition by certain amino acids. Scand J Clin Lab Invest 37(6):477–486

    PubMed  CAS  Google Scholar 

  • Montagna M, Montillo M, Avanzini MA, Tinelli C, Tedeschi A, Visai L, Ricci F, Vismara E, Morra E, Regazzi M (2011) Relationship between pharmacokinetic profile of subcutaneously administered alemtuzumab and clinical response in patients with chronic lymphocytic leukemia. Haematologica 96(6):932–936

    PubMed  CAS  Google Scholar 

  • Naruki Y, Carrasquillo JA, Reynolds JC, Maloney PJ, Frincke JM, Neumann RD, Larson SM (1990) Differential cellular catabolism of 111In, 90Y and 125I radiolabeled T101 anti-CD5 monoclonal antibody. Int J Rad Appl Instrum B 17(2):201–207

    PubMed  CAS  Google Scholar 

  • Navath RS, Kurtoglu YE, Wang B, Kannan S, Romero R, Kannan RM (2008) Dendrimer−drug conjugates for tailored intracellular drug release based on glutathione levels. Bioconjug Chem 19(12):2446–2455

    PubMed  CAS  Google Scholar 

  • Negri L, Lattanzi R, Tabacco F, Scolaro B, Rocchi R (1998) Glycodermorphins: opioid peptides with potent and prolonged analgesic activity and enhanced blood–brain barrier penetration. Br J Pharmacol 124(7):1516–1522

    PubMed  CAS  Google Scholar 

  • Ovadia O, Linde Y, Haskell-Luevano C, Dirain ML, Sheynis T, Jelinek R, Gilon C, Hoffman A (2010) The effect of backbone cyclization on PK/PD properties of bioactive peptide-peptoid hybrids: the melanocortin agonist paradigm. Bioorg Med Chem 18(2):580–589

    PubMed  CAS  Google Scholar 

  • Peter-Katalinic J (2005) Methods in enzymology: O-glycosylation of proteins. Methods Enzymol 405:139–171

    PubMed  CAS  Google Scholar 

  • Pipe SW, High K, Ohashi K, Ural A, Lillicrap D (2008) Progress in the molecular biology of inherited bleeding disorders. Haemophilia 14:130–137

    PubMed  Google Scholar 

  • Rabuka D (2010) Chemoenzymatic methods for site-specific protein modification. Curr Opin Chem Biol 14(6):790–796

    PubMed  CAS  Google Scholar 

  • Rasmussen JR (1992) Effect of glycosylation on protein function. Curr Opin Struct Biol 2(5):682–686

    CAS  Google Scholar 

  • Roberts M, Bentley M, Harris J (2002) Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 54(4):459–476

    PubMed  CAS  Google Scholar 

  • Rustom R, Maltby P, Grime J, Stockdale H, Critchley M, Bone J (1992) Effects of lysine infusion on the renal metabolism of aprotinin (Trasylol) in man. Clin Sci (Lond) 83(3):295–299

    CAS  Google Scholar 

  • Saenko E, Pipe SW (2006) Strategies towards a longer acting factor VIII. Haemophilia 12:42–51

    PubMed  CAS  Google Scholar 

  • Sakahara H, Saga T, Endo K, Hattori N, Hosono M, Kobayashi H, Shirato M, Yamamuro T, Toyama S, Arano Y (1993) In vivo instability of reduction-mediated 99mTc-labeled monoclonal antibody. Nucl Med Biol 20(5):617–623

    PubMed  CAS  Google Scholar 

  • Sans T, Joven J, Vilella E, Masdeu G, Farre M (2000) Pharmacokinetics of several subcutaneous doses of erythropoietin: potential implications for blood transfusion. Clin Exp Pharmacol Physiol 27(3):179–184

    PubMed  CAS  Google Scholar 

  • Sarkar A, Wintrode PL (2011) Effects of glycosylation on the stability and flexibility of a metastable protein: the human serpin alpha(1)-antitrypsin. Int J Mass Spectrom 302(1–3):69–75. doi:10.1016/j.ijms.2010.08.003

    PubMed  CAS  Google Scholar 

  • Sasaki H, Ichikawa M, Yamanura K, Nishida K, Nakamura J (1997) Ocular membrane permeability of hydrophilic drugs for ocular peptide delivery. J Pharm Pharmacol 49(2):135–139

    PubMed  CAS  Google Scholar 

  • Schulte S (2008) Use of albumin fusion technology to prolong the half-life of recombinant factor VIIa. Thromb Res 122:S14–S19

    PubMed  CAS  Google Scholar 

  • Sears P, Wong CH (1998) Enzyme action in glycoprotein synthesis. Cell Mol Life Sci 54(3):223–252

    PubMed  CAS  Google Scholar 

  • Shahnaz G, Iqbal J, Rahmat D, Perera G, Laffleur F, Rossi D, Bernkop-Schnürch A (2012) Development and in vivo characterization of a novel peptide drug delivery system providing extended plasma half-life. J Control Release 157(3):375–382

    PubMed  CAS  Google Scholar 

  • Sharifi J, Khawli LA, Hornick JL, Epstein AL (1998) Improving monoclonal antibody pharmacokinetics via chemical modification. Q J Nucl Med 42(4):242–249

    PubMed  CAS  Google Scholar 

  • Sheffield WP, Smith I, Syed S, Bhakta V (2001) Prolonged in vivo anticoagulant activity of a hirudin–albumin fusion protein secreted from Pichia pastoris. Blood Coagul Fibrinolysis 12(6):433

    PubMed  CAS  Google Scholar 

  • Shental-Bechor D, Levy Y (2008) Effect of glycosylation on protein folding: a close look at thermodynamic stabilization. Proc Natl Acad Sci USA 105(24):8256

    PubMed  CAS  Google Scholar 

  • Siekmeier R, Scheuch G (2008) Inhaled insulin—does it become reality. J Physiol Pharmacol 59(Suppl 6):81–113

    PubMed  Google Scholar 

  • Sinclair AM, Elliott S (2005) Glycoengineering: the effect of glycosylation on the properties of therapeutic proteins. J Pharm Sci 94(8):1626–1635

    PubMed  CAS  Google Scholar 

  • Solá RJ, Griebenow K (2010) Glycosylation of therapeutic proteins: an effective strategy to optimize efficacy. BioDrugs 24(1):9–21

    PubMed  Google Scholar 

  • Straub SG, Sharp GWG (2002) Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab Res Rev 18(6):451–463

    PubMed  CAS  Google Scholar 

  • Sumpio B, Maack T (1982) Kinetics, competition, and selectivity of tubular absorption of proteins. Am J Physiol 243(4):F379–F392

    PubMed  CAS  Google Scholar 

  • Supersaxo A, Hein WR, Steffen H (1990) Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharm Res 7(2):167–169

    PubMed  CAS  Google Scholar 

  • Tabrizi M, Bornstein GG, Suria H (2010) Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease. AAPS J 12(1):33–43

    PubMed  CAS  Google Scholar 

  • Tomatis R, Marastoni M, Balboni G, Guerrini R, Capasso A, Sorrentino L, Santagada V, Caliendo G, Lazarus LH, Salvadori S (1997) Synthesis and pharmacological activity of deltorphin and dermorphin-related glycopeptides. J Med Chem 40(18):2948–2952

    PubMed  CAS  Google Scholar 

  • Toon S (1996) The relevance of pharmacokinetics in the development of biotechnology products. Eur J Drug Metab Pharmacokinet 21(2):93–103

    PubMed  CAS  Google Scholar 

  • Turchinovich A, Zoidl G, Dermietzel R (2010) Non-viral siRNA delivery into the mouse retina in vivo. BMC Ophthalmol 10:25. doi:10.1186/1471-2415-10-25

    PubMed  Google Scholar 

  • Urva SR, Balthasar JP (2010) Target mediated disposition of T84.66, a monoclonal anti-CEA antibody: application in the detection of colorectal cancer xenografts. MAbs 2:67–72

    PubMed  Google Scholar 

  • Volkin DB, Sanyal G, Burke CJ, Middaugh CR (2002) Preformulation studies as an essential guide to formulation development and manufacture of protein pharmaceuticals. Pharm Biotechnol 14:1–46

    PubMed  CAS  Google Scholar 

  • Vugmeyster Y, DeFranco D, Pittman DD, Xu X (2010a) Pharmacokinetics and lung distribution of a humanized anti-RAGE antibody in wild-type and RAGE−/− mice. MAbs 2:571–575

    PubMed  Google Scholar 

  • Vugmeyster Y, DeFranco D, Szklut P, Wang Q, Xu X (2010b) Biodistribution of [125I]-labeled therapeutic proteins: application in protein drug development beyond oncology. J Pharm Sci 99(2):1028–1045

    PubMed  CAS  Google Scholar 

  • Vugmeyster Y, Xu X, Theil F, Khawli LA, Leach MW (2012) Pharmacokinetics and toxicology of therapeutic proteins: advances and challenges. World J Biol Chem 3(4):73–92

    PubMed  Google Scholar 

  • Wang YJ, Hao SJ, Liu YD, Hu T, Zhang GF, Zhang X, Qi QS, Ma GH, Su ZG (2010) PEGylation markedly enhances the in vivo potency of recombinant human non-glycosylated erythropoietin: a comparison with glycosylated erythropoietin. J Control Release 145(3):306–313

    PubMed  CAS  Google Scholar 

  • Weimer T, Wormsbacher W, Kronthaler U, Lang W, Liebing U, Schulte S (2008) Prolonged in vivo half-life of factor VIIa by fusion to albumin. Thromb Haemost 99(4):659–667

    PubMed  CAS  Google Scholar 

  • Witt KA, Gillespie TJ, Huber JD, Egleton RD, Davis TP (2001) Peptide drug modifications to enhance bioavailability and blood–brain barrier permeability. Peptides 22(12):2329–2343

    PubMed  CAS  Google Scholar 

  • Wochner RD, Strober W, Waldmann TA (1967) The role of the kidney in the catabolism of Bence Jones proteins and immunoglobulin fragments. J Exp Med 126(2):207–221

    PubMed  CAS  Google Scholar 

  • Xie D, Yao C, Wang L, Min W, Xu J, Xiao J, Huang M, Chen B, Liu B, Li X (2010) An albumin-conjugated peptide exhibits potent anti-HIV activity and long in vivo half-life. Antimicrob Agents Chemother 54(1):191–196

    PubMed  CAS  Google Scholar 

  • Zhang MQ, Wilkinson B (2007) Drug discovery beyond the ‘rule-of-five’. Curr Opin Biotechnol 18(6):478–488

    PubMed  CAS  Google Scholar 

Download references

Conflict of interest

There is no conflict of interest with any person or financial and institutional body.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Aliasgar Shahiwala.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Swami, R., Shahiwala, A. Impact of physiochemical properties on pharmacokinetics of protein therapeutics. Eur J Drug Metab Pharmacokinet 38, 231–239 (2013). https://doi.org/10.1007/s13318-013-0126-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13318-013-0126-0

Keywords

Navigation