The AAPS Journal

, Volume 17, Issue 1, pp 134–143 | Cite as

Strategic Approaches to Optimizing Peptide ADME Properties

Review Article Theme: Preclinical Peptide Developability Assessment
Part of the following topical collections:
  1. Theme: Preclinical Peptide Developability Assessment


Development of peptide drugs is challenging but also quite rewarding. Five blockbuster peptide drugs are currently on the market, and six new peptides received first marketing approval as new molecular entities in 2012. Although peptides only represent 2% of the drug market, the market is growing twice as quickly and might soon occupy a larger niche. Natural peptides typically have poor absorption, distribution, metabolism, and excretion (ADME) properties with rapid clearance, short half-life, low permeability, and sometimes low solubility. Strategies have been developed to improve peptide drugability through enhancing permeability, reducing proteolysis and renal clearance, and prolonging half-life. In vivo, in vitro, and in silico tools are available to evaluate ADME properties of peptides, and structural modification strategies are in place to improve peptide developability.


ADME peptides pharmacokinetics proteolysis renal clearance 



The author would like to thank Karen Atkinson for editing the manuscript; Angela Doran, Angela Wolford, and Amit Kalgutkar for the study on peptide PK prediction; and Larry Tremaine, Tess Wilson, and Charlotte Allerton for their leadership and support.


  1. 1.
    Hopkins AL, Groom CR. Opinion: the druggable genome. Nat Rev Drug Discov. 2002;1(9):727–30.PubMedGoogle Scholar
  2. 2.
    Gongora-Benitez M, Tulla-Puche J, Albericio F. Multifaceted roles of disulfide bonds. Peptides as therapeutics. Chem Rev (Washington, DC, U S). 2014;114(2):901–26.Google Scholar
  3. 3.
    Sun L. Peptide-based drug development. Mod Chem Appl. 2013;1(1):1–2.Google Scholar
  4. 4.
    Goodwin D, Simerska P, Toth I. Peptides as therapeutics with enhanced bioactivity. Curr Med Chem. 2012;19(26):4451–61.PubMedGoogle Scholar
  5. 5.
    Craik DJ, Fairlie DP, Liras S, Price D. The future of peptide-based drugs. Chem Biol Drug Des. 2013;81(1):136–47.PubMedGoogle Scholar
  6. 6.
    Kaspar AA, Reichert JM. Future directions for peptide therapeutics development. Drug Discov Today. 2013;18(17–18):807–17.PubMedGoogle Scholar
  7. 7.
    Vlieghe P, Lisowski V, Martinez J, Khrestchatisky M. Synthetic therapeutic peptides: science and market. Drug Discov Today. 2010;15(1/2):40–56.PubMedGoogle Scholar
  8. 8.
    Ladner RC, Sato AK, Gorzelany J, De Souza M. Phage display-derived peptides as therapeutic alternatives to antibodies. Drug Discov Today. 2004;9(12):525–9.PubMedGoogle Scholar
  9. 9.
    Lax R, Meenan C. Challenges for therapeutic peptides part 1: on the inside, looking out. Innovations Pharm Technol. 2012;42:54–6.Google Scholar
  10. 10.
    Lax R, Meenan C. Challenges for therapeutic peptides part 2: delivery systems. Innovations Pharm Technol. 2012;43:42–4. 6.Google Scholar
  11. 11.
    Bray BL. Innovation: large-scale manufacture of peptide therapeutics by chemical synthesis. Nat Rev Drug Discov. 2003;2(7):587–93.PubMedGoogle Scholar
  12. 12.
    Edmonds DJ, Price DA. Oral GLP-1 modulators for the treatment of diabetes. Annu Rep Med Chem. 2013;48:119–30.Google Scholar
  13. 13.
    Rezai T, Bock JE, Zhou MV, Kalyanaraman C, Lokey RS, Jacobson MP. Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: successful in silico prediction of the relative permeabilities of cyclic peptides. J Am Chem Soc. 2006;128(43):14073–80.PubMedGoogle Scholar
  14. 14.
    Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral delivery of peptide and protein drugs. Crit Rev Ther Drug Carrier Syst. 2003;20(2–3):153–214.PubMedGoogle Scholar
  15. 15.
    Diao L, Meibohm B. Pharmacokinetics and pharmacokinetic-pharmacodynamic correlations of therapeutic peptides. Clin Pharmacokinet. 2013;52(10):855–68.PubMedGoogle Scholar
  16. 16.
    Rand AC, Leung SSF, Eng H, Rotter CJ, Sharma R, Kalgutkar AS, et al. Optimizing PK properties of cyclic peptides: the effect of side chain substitutions on permeability and clearance. Med Chem Comm. 2012;3(10):1282–9.Google Scholar
  17. 17.
    Werle M, Bernkop-Schnuerch A. Strategies to improve plasma half life time of peptide and protein drugs. Amino Acids. 2006;30(4):351–67.PubMedGoogle Scholar
  18. 18.
    Zhou XH, Li Wan Po A. Peptide and protein drugs: II. Non-parenteral routes of delivery. Int J Pharm. 1991;75(2–3):117–30.Google Scholar
  19. 19.
    Hellriegel ET, Bjornsson TD, Hauck WW. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin Pharmacol Ther (St Louis). 1996;60(6):601–7.Google Scholar
  20. 20.
    Maher S, Brayden DJ. Overcoming poor permeability: translating permeation enhancers for oral peptide delivery. Drug Discov Today: Technol. 2012;9(2):e113–e9.Google Scholar
  21. 21.
    Chin J, Foyez Mahmud KA, Kim SE, Park K, Byun Y. Insight of current technologies for oral delivery of proteins and peptides. Drug Discov Today: Technol. 2012;9(2):e105–e12.Google Scholar
  22. 22.
    Lin JH. Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies. Curr Drug Metab. 2009;10(7):661–91.PubMedGoogle Scholar
  23. 23.
    Periti P, Mazzei T, Mini E. Clinical pharmacokinetics of depot leuprorelin. Clin Pharmacokinet. 2002;41(7):485–504.PubMedGoogle Scholar
  24. 24.
    Munegumi T. Hydrophobicity of peptides containing D-amino acids. Chem Biodivers. 2010;7(6):1670–9.PubMedGoogle Scholar
  25. 25.
    Ano R, Kimura Y, Shima M, Matsuno R, Ueno T, Akamatsu M. Relationships between structure and high-throughput screening permeability of peptide derivatives and related compounds with artificial membranes: application to prediction of Caco-2 cell permeability. Bioorg Med Chem. 2004;12(1):257–64.PubMedGoogle Scholar
  26. 26.
    Kramer SD, Wunderli-Allenspach H. No entry for TAT(44–57) into liposomes and intact MDCK cells: novel approach to study membrane permeation of cell-penetrating peptides. Biochim Biophys Acta Biomembr. 2003;1609(2):161–9.Google Scholar
  27. 27.
    Tang F, Borchardt RT. Characterization of the efflux transporter(s) responsible for restricting intestinal mucosa permeation of the coumarinic acid-based cyclic prodrug of the opioid peptide DADLE. Pharm Res. 2002;19(6):787–93.PubMedGoogle Scholar
  28. 28.
    Ano R, Kimura Y, Urakami M, Shima M, Matsuno R, Ueno T, et al. Relationship between structure and permeability of dipeptide derivatives containing tryptophan and related compounds across human intestinal epithelial (Caco-2) cells. Bioorg Med Chem. 2004;12(1):249–55.PubMedGoogle Scholar
  29. 29.
    Stevenson CL, Augustijns PF, Hendren RW. Use of Caco-2 cells and LC/MS/MS to screen a peptide combinatorial library for permeable structures. Int J Pharm. 1999;177(1):103–15.PubMedGoogle Scholar
  30. 30.
    Beck JG, Chatterjee J, Laufer B, Kiran MU, Frank AO, Neubauer S, et al. Intestinal permeability of cyclic peptides: common key backbone motifs identified. J Am Chem Soc. 2012;134(29):12125–33.PubMedGoogle Scholar
  31. 31.
    Bhardwaj RK, Herrera-Ruiz D, Sinko PJ, Gudmundsson OS, Knipp G. Delineation of human peptide transporter 1 (hPepT1)-mediated uptake and transport of substrates with varying transporter affinities utilizing stably transfected hPepT1/Madin-Darby canine kidney clones and Caco-2 cells. J Pharmacol Exp Ther. 2005;314(3):1093–100.PubMedGoogle Scholar
  32. 32.
    Faria TN, Timoszyk JK, Stouch TR, Vig BS, Landowski CP, Amidon GL, et al. A novel high-throughput PepT1 transporter assay differentiates between substrates and antagonists. Mol Pharm. 2004;1(1):67–76.PubMedGoogle Scholar
  33. 33.
    Balimane PV, Chong S, Patel K, Quan Y, Timoszyk J, Han Y-H, et al. Peptide transporter substrate identification during permeability screening in drug discovery: comparison of transfected MDCK-hPepT1 cells to Caco-2 cells. Arch Pharmacal Res. 2007;30(4):507–18.Google Scholar
  34. 34.
    Vadlapudi AD, Vadlapatla RK, Mitra AK. Sodium dependent multivitamin transporter (SMVT): a potential target for drug delivery. Curr Drug Targets. 2012;13(7):994–1003.PubMedGoogle Scholar
  35. 35.
    Stenberg P, Luthman K, Artursson P. Prediction of membrane permeability to peptides from calculated dynamic molecular surface properties. Pharm Res. 1999;16(2):205–12.PubMedGoogle Scholar
  36. 36.
    Rafi SB, Hearn BR, Vedantham P, Jacobson MP, Renslo AR. Predicting and improving the membrane permeability of peptidic small molecules. J Med Chem. 2012;55(7):3163–9.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Jappar D, Hu Y, Smith DE. Effect of dose escalation on the in vivo oral absorption and disposition of glycylsarcosine in wild-type and Pept1 knockout mice. Drug Metab Dispos. 2011;39(12):2250–7.PubMedCentralPubMedGoogle Scholar
  38. 38.
    Li W, Zhang J, Tse FLS. Handbook of LC-MS bioanalysis: best practices, experimental protocols, and regulations 2013.Google Scholar
  39. 39.
    Letzel T, Editor. Protein and peptide analysis by LC-MS: experimental strategies. [In: RSC Chromatogr. Monogr., 2011; 15]2011. 172 pp.Google Scholar
  40. 40.
    van den Broek I, Sparidans RW, Schellens JHM, Beijnen JH. Quantitative bioanalysis of peptides by liquid chromatography coupled to (tandem) mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2008;872(1–2):1–22.Google Scholar
  41. 41.
    Li W, Zhang J, Tse FLS. Strategies in quantitative LC-MS/MS analysis of unstable small molecules in biological matrices. Biomed Chromatogr. 2011;25(1–2):258–77.PubMedGoogle Scholar
  42. 42.
    Nowatzke WL, Rogers K, Wells E, Bowsher RR, Ray C, Unger S. Unique challenges of providing bioanalytical support for biological therapeutic pharmacokinetic programs. Bioanalysis. 2011;3(5):509–21.PubMedGoogle Scholar
  43. 43.
    Kuhn B, Mohr P, Stahl M. Intramolecular hydrogen bonding in medicinal chemistry. J Med Chem. 2010;53(6):2601–11.PubMedGoogle Scholar
  44. 44.
    Lokey RS. Testing the conformational hypothesis of membrane permeability using cyclic peptide diastereomers. Abstracts of Papers, 232nd ACS National Meeting, San Francisco, CA, United States, Sept 10–14, 2006. 2006:BIOL-167.Google Scholar
  45. 45.
    Rezai T, Yu B, Millhauser GL, Jacobson MP, Lokey RS. Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers. J Am Chem Soc. 2006;128(8):2510–1.PubMedGoogle Scholar
  46. 46.
    White TR, Renzelman CM, Rand AC, Rezai T, McEwen CM, Gelev VM, et al. On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat Chem Biol. 2011;7(11):810–7.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Alex A, Millan DS, Perez M, Wakenhut F, Whitlock GA. Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space. Med Chem Comm. 2011;2(7):669–74.Google Scholar
  48. 48.
    Milletti F. Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov Today. 2012;17(15–16):850–60.PubMedGoogle Scholar
  49. 49.
    Tressel SL, Koukos G, Tchernychev B, Jacques SL, Covic L, Kuliopulos A. Pharmacology, biodistribution, and efficacy of GPCR-based pepducins in disease models. Methods Mol Biol (N Y, NY, U S). 2011;683:259–75. Cell-Penetrating Peptides.Google Scholar
  50. 50.
    Wang J, Shen D, Shen W-C. Preparation, purification, and characterization of a reversibly lipidized desmopressin with potentiated antidiuretic activity. Pharm Res. 1999;16(11):1674–9.PubMedGoogle Scholar
  51. 51.
    Wang J, Chow D, Heiati H, Shen W-C. Reversible lipidization for the oral delivery of salmon calcitonin. J Control Release. 2003;88(3):369–80.PubMedGoogle Scholar
  52. 52.
    Wang J, Shen W-C. Gastric retention and stability of lipidized Bowman-Birk protease inhibitor in mice. Int J Pharm. 2000;204(1–2):111–6.PubMedGoogle Scholar
  53. 53.
    Chae SY, Jin C-H, Shin HJ, Youn YS, Lee S, Lee KC. Preparation, characterization, and application of biotinylated and biotin-PEGylated glucagon-like peptide-1 analogues for enhanced oral delivery. Bioconjugate Chem. 2008;19(1):334–41.Google Scholar
  54. 54.
    Clardy-James S, Chepurny OG, Leech CA, Holz GG, Doyle RP. Synthesis, characterization and pharmacodynamics of vitamin-B12-conjugated glucagon-like peptide-1. ChemMedChem. 2013;8(4):582–6.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Clardy SM, Allis DG, Fairchild TJ, Doyle RP. Vitamin B12 in drug delivery: breaking through the barriers to a B12 bioconjugate pharmaceutical. Expert Opin Drug Deliv. 2011;8(1):127–40.PubMedGoogle Scholar
  56. 56.
    Shaji J, Patole V. Protein and peptide drug delivery: oral approaches. Indian J Pharm Sci. 2008;70(3):269–77.PubMedCentralPubMedGoogle Scholar
  57. 57.
    Aungst BJ. Intestinal permeation enhancers. J Pharm Sci. 2000;89(4):429–42.PubMedGoogle Scholar
  58. 58.
    Whitehead K, Karr N, Mitragotri S. Safe and effective permeation enhancers for oral drug delivery. Pharm Res. 2008;25(8):1782–8.PubMedGoogle Scholar
  59. 59.
    LeCluyse EL, Sutton SC. In vitro models for selection of development candidates. Permeability studies to define mechanisms of absorption enhancement. Adv Drug Deliv Rev. 1997;23(1–3):163–83.Google Scholar
  60. 60.
    Wang X, Maher S, Brayden DJ. Restoration of rat colonic epithelium after in situ intestinal instillation of the absorption promoter, sodium caprate. Ther Deliv. 2010;1(1):75–82.PubMedGoogle Scholar
  61. 61.
    Goldberg M, Gomez-Orellana I. Challenges for the oral delivery of macromolecules. Nat Rev Drug Discov. 2003;2(4):289–95.PubMedGoogle Scholar
  62. 62.
    Puente XS, Gutierrez-Fernandez A, Ordonez GR, Hillier LW, Lopez-Otin C. Comparative genomic analysis of human and chimpanzee proteases. Genomics. 2005;86(6):638–47.PubMedGoogle Scholar
  63. 63.
    Woodley JF. Enzymatic barriers for GI peptide and protein delivery. Crit Rev Ther Drug Carrier Syst. 1994;11(2–3):61–95.PubMedGoogle Scholar
  64. 64.
    Powell MF, Grey H, Gaeta F, Sette A, Colon S. Peptide stability in drug development: a comparison of peptide reactivity in different biological media. J Pharm Sci. 1992;81(8):731–5.PubMedGoogle Scholar
  65. 65.
    Powell MF, Stewart T, Otvos Jr L, Urge L, Gaeta FCA, Sette A, et al. Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. Pharm Res. 1993;10(9):1268–73.PubMedGoogle Scholar
  66. 66.
    Noto PB, Abbadessa G, Cassone M, Mateo GD, Agelan A, Wade JD, et al. Alternative stabilities of a proline-rich antibacterial peptide in vitro and in vivo. Protein Sci. 2008;17(7):1249–55.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Eng H, Sharma R, McDonald TS, Landis MS, Stevens BD, Kalgutkar AS. Pharmacokinetics and metabolism studies on the glucagon-like peptide-1 (GLP-1)-derived metabolite GLP-1(9–36)amide in male Beagle dogs. Xenobiotica. 2014;44(9):842–8.PubMedGoogle Scholar
  68. 68.
    Sharma R, McDonald TS, Eng H, Limberakis C, Stevens BD, Patel S, et al. In vitro metabolism of the glucagon-like peptide-1 (GLP-1)-derived metabolites GLP-1(9–36)amide and GLP-1(28–36)amide in mouse and human hepatocytes. Drug Metab Dispos. 2013;41(12):2148–57.PubMedGoogle Scholar
  69. 69.
    Adessi C, Soto C. Converting a peptide into a drug: strategies to improve stability and bioavailability. Curr Med Chem. 2002;9(9):963–78.PubMedGoogle Scholar
  70. 70.
    Linde Y, Ovadia O, Safrai E, Xiang Z, Portillo FP, Shalev DE, et al. Structure-activity relationship and metabolic stability studies of backbone cyclization and N-methylation of melanocortin peptides. Biopolymers. 2008;90(5):671–82.PubMedCentralPubMedGoogle Scholar
  71. 71.
    Ovadia O, Linde Y, Haskell-Luevano C, Dirain ML, Sheynis T, Jelinek R, et al. The effect of backbone cyclization on PK/PD properties of bioactive peptide-peptoid hybrids: the melanocortin agonist paradigm. Bioorg Med Chem. 2010;18(2):580–9.PubMedGoogle Scholar
  72. 72.
    Hess S, Linde Y, Ovadia O, Safrai E, Shalev DE, Swed A, et al. Backbone cyclic peptidomimetic melanocortin-4 receptor agonist as a novel orally administrated drug lead for treating obesity. J Med Chem. 2008;51(4):1026–34.PubMedGoogle Scholar
  73. 73.
    Byk G, Halle D, Zeltser I, Bitan G, Selinger Z, Gilon C. Synthesis and biological activity of NK-1 selective, N-backbone cyclic analogs of the C-terminal hexapeptide of substance P. J Med Chem. 1996;39(16):3174–8.PubMedGoogle Scholar
  74. 74.
    Pollaro L, Heinis C. Strategies to prolong the plasma residence time of peptide drugs. Med Chem Comm. 2010;1(5):319–24.Google Scholar
  75. 75.
    Pisal DS, Kosloski MP, Balu-Iyer SV. Delivery of therapeutic proteins. J Pharm Sci. 2010;99(6):2557–75.PubMedCentralPubMedGoogle Scholar
  76. 76.
    Sato AK, Viswanathan M, Kent RB, Wood CR. Therapeutic peptides: technological advances driving peptides into development. Curr Opin Biotechnol. 2006;17(6):638–42.PubMedGoogle Scholar
  77. 77.
    John H, Maronde E, Forssmann W-G, Meyer M, Adermann K. N-terminal acetylation protects glucagon-like peptide GLP-1-(7–34)-amide from DPP-IV-mediated degradation retaining cAMP-and insulin releasing capacity. Eur J Med Res. 2008;13(2):73–8.PubMedGoogle Scholar
  78. 78.
    Stroemstedt AA, Pasupuleti M, Schmidtchen A, Malmsten M. Evaluation of strategies for improving proteolytic resistance of antimicrobial peptides by using variants of EFK17, an internal segment of LL-37. Antimicrob Agents Chemother. 2009;53(2):593–602.Google Scholar
  79. 79.
    Ferdinandi ES, Brazeau P, High K, Procter B, Fennell S, Dubreuil P. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic Clin Pharmacol Toxicol. 2007;100(1):49–58.PubMedGoogle Scholar
  80. 80.
    Sharman A, Low J. Vasopressin and its role in critical care. Contin Educ Anaesth, Crit Care Pain. 2008;8(4):134–7.Google Scholar
  81. 81.
    Agerso H, Larsen LS, Riis A, Lovgren U, Karlsson MO, Senderovitz T. Pharmacokinetics and renal excretion of desmopressin after intravenous administration to healthy subjects and renally impaired patients. Br J Clin Pharmacol. 2004;58(4):352–8.PubMedCentralPubMedGoogle Scholar
  82. 82.
    Harris AG. Somatostatin and somatostatin analogues: pharmacokinetics and pharmacodynamic effects. Gut. 1994;35(3 Suppl):S1–4.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Chen S, Gfeller D, Buth SA, Michielin O, Leiman PG, Heinis C. Improving binding affinity and stability of peptide ligands by substituting glycines with D-amino acids. Chem Bio Chem. 2013;14(11):1316–22.PubMedGoogle Scholar
  84. 84.
    Tugyi R, Uray K, Ivan D, Fellinger E, Perkins A, Hudecz F. Partial D-amino acid substitution: improved enzymatic stability and preserved Ab recognition of a MUC2 epitope peptide. Proc Natl Acad Sci U S A. 2005;102(2):413–8.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Darlak K, Benovitz DE, Spatola AF, Grzonka Z. Dermorphin analogs: resistance to in vitro enzymatic degradation is not always increased by additional D-amino acid substitutions. Biochem Biophys Res Commun. 1988;156(1):125–30.PubMedGoogle Scholar
  86. 86.
    Rafferty B, Coy DH, Poole S. Pharmacokinetic evaluation of superactive analogues of growth hormone-releasing factor (1–29)-amide. Peptides. 1988;9(1):207–9.PubMedGoogle Scholar
  87. 87.
    Nattel S, Carlsson L. Innovative approaches to anti-arrhythmic drug therapy. Nat Rev Drug Discov. 2006;5(12):1034–49.PubMedGoogle Scholar
  88. 88.
    Welch BD, Francis JN, Redman JS, Paul S, Weinstock MT, Reeves JD, et al. Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance. J Virol. 2010;84(21):11235–44.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Verschraegen CF, Westphalen S, Hu W, Loyer E, Kudelka A, Volker P, et al. Phase II study of cetrorelix, a luteinizing hormone-releasing hormone antagonist in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2003;90(3):552–9.PubMedGoogle Scholar
  90. 90.
    Heredi-Szabo K, Murphy RF, Lovas S. Is IGnRH-III the most potent GnRH analog containing only natural amino acids that specifically inhibits the growth of human breast cancer cells? J Pept Sci. 2006;12(11):714–20.PubMedGoogle Scholar
  91. 91.
    Raun K, Hansen BS, Johansen NL, Thogersen H, Madsen K, Ankersen M, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552–61.PubMedGoogle Scholar
  92. 92.
    Gobburu JVS, Agerso H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999;16(9):1412–6.PubMedGoogle Scholar
  93. 93.
    Weber SJ, Greene DL, Hruby VJ, Yamamura HI, Porreca F, Davis TP. Whole body and brain distribution of [3H]cyclic [D-Pen2, D-Pen5]enkephalin after intraperitoneal, intravenous, oral and subcutaneous administration. J Pharmacol Exp Ther. 1992;263(3):1308–16.PubMedGoogle Scholar
  94. 94.
    Tugyi R, Mezo G, Fellinger E, Andreu D, Hudecz F. The effect of cyclization on the enzymatic degradation of herpes simplex virus glycoprotein D derived epitope peptide. J Pept Sci. 2005;11(10):642–9.PubMedGoogle Scholar
  95. 95.
    Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright RD, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science (Washington, DC, U S). 2004;305(5689):1466–70.Google Scholar
  96. 96.
    Bernal F, Tyler AF, Korsmeyer SJ, Walensky LD, Verdine GL. Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide [Erratum to document cited in CA146:397011]. J Am Chem Soc. 2007;129(16):5298.Google Scholar
  97. 97.
    Bird GH, Madani N, Perry AF, Princiotto AM, Supko JG, He X, et al. Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc Natl Acad Sci U S A. 2010;107(32):14093–8. S/1-S/8.PubMedCentralPubMedGoogle Scholar
  98. 98.
    Grigoryev Y. Stapled peptide to enter human testing, but affinity questions remain. Nat Med (N Y, NY, U S). 2013;19(2):120.Google Scholar
  99. 99.
    Czock D, Keller F, Seidling HM. Pharmacokinetic predictions for patients with renal impairment: focus on peptides and protein drugs. Br J Clin Pharmacol. 2012;74(1):66–74.PubMedCentralPubMedGoogle Scholar
  100. 100.
    Verbeeck RK, Musuamba FT. Pharmacokinetics and dosage adjustment in patients with renal dysfunction. Eur J Clin Pharmacol. 2009;65(8):757–73.PubMedGoogle Scholar
  101. 101.
    Chanson P, Timsit J, Harris AG. Clinical pharmacokinetics of octreotide. Therapeutic applications in patients with pituitary tumours. Clin Pharmacokinet. 1993;25(5):375–91.PubMedGoogle Scholar
  102. 102.
    Kutz K, Nuesch E, Rosenthaler J. Pharmacokinetics of SMS 201–995 in healthy subjects. Scand J Gastroenterol Suppl. 1986;119:65–72.PubMedGoogle Scholar
  103. 103.
    Malm-Erjefalt M, Bjoernsdottir I, Vanggaard J, Helleberg H, Larsen U, Oosterhuis B, et al. Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos. 2010;38(11):1944–53.PubMedGoogle Scholar
  104. 104.
    Hou J, Manaenko A, Hakon J, Hansen-Schwartz J, Tang J, Zhang JH. Liraglutide, a long-acting GLP-1 mimetic, and its metabolite attenuate inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab. 2012;32(12):2201–10.PubMedCentralPubMedGoogle Scholar
  105. 105.
    Levy Odile E, Jodka Carolyn M, Ren Shijun S, Mamedova L, Sharma A, Samant M, et al. Novel exenatide analogs with peptidic albumin binding domains: potent anti-diabetic agents with extended duration of action. PLoS One. 2014;9(2):e87704.PubMedCentralPubMedGoogle Scholar
  106. 106.
    Lindgren J, Refai E, Zaitsev Sergei V, Abrahmsen L, Berggren P-O, Karlstrom AE. A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life. Biopolymers. 2014;102(3):252–9.PubMedGoogle Scholar
  107. 107.
    Angelini A, Morales-Sanfrutos J, Diderich P, Chen S, Heinis C. Bicyclization and tethering to albumin yields long-acting peptide antagonists. J Med Chem. 2012;55(22):10187–97.PubMedGoogle Scholar
  108. 108.
    Bronson J, Black A, Dhar TGM, Ellsworth BA, Merritt JR. To market, to market—2012. Annu Rep Med Chem. 2013;48:471–546.Google Scholar
  109. 109.
    Baggio LL, Huang Q, Cao X, Drucker DJ. An albumin-exendin-4 conjugate engages central and peripheral circuits regulating murine energy and glucose homeostasis. Gastroenterology. 2008;134(4):1137–47.PubMedGoogle Scholar
  110. 110.
    Poole RM, Nowlan ML. Albiglutide: first global approval. Drugs. 2014:Ahead of Print.Google Scholar
  111. 111.
    Pratley RE, Nauck MA, Barnett AH, Feinglos MN, Ovalle F, Harman-Boehm I, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2(4):289–97.PubMedGoogle Scholar
  112. 112.
    Delaforgea M, Bouille G, Jaouen M, Jankowski CK, Lamouroux C, Bensoussan C. Recognition and oxidative metabolism of cyclodipeptides by hepatic cytochrome P450. Peptides (N Y, NY, U S). 2001;22(4):557–65.Google Scholar
  113. 113.
    Wacher VJ, Silverman JA, Zhang Y, Benet LZ. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharm Sci. 1998;87(11):1322–30.PubMedGoogle Scholar
  114. 114.
    Pekol T, Daniels JS, Labutti J, Parsons I, Nix D, Baronas E, et al. Human metabolism of the proteasome inhibitor bortezomib: identification of circulating metabolites. Drug Metab Dispos. 2005;33(6):771–7.PubMedGoogle Scholar
  115. 115.
    Di L, Feng B, Goosen TC, Lai Y, Steyn SJ, Varma MV, et al. A perspective on the prediction of drug pharmacokinetics and disposition in drug research and development. Drug Metab Dispos. 2013;41(12):1975–93.PubMedGoogle Scholar
  116. 116.
    Wang W, Prueksaritanont T. Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited. Biopharm Drug Dispos. 2010;31(4):253–63.PubMedGoogle Scholar
  117. 117.
    Mordenti J, Chen SA, Moore JA, Ferraiolo BL, Green JD. Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm Res. 1991;8(11):1351–9.PubMedGoogle Scholar
  118. 118.
    Richter WF, Gallati H, Schiller C-D. Animal pharmacokinetics of the tumor necrosis factor receptor-immunoglobulin fusion protein lenercept and their extrapolation to humans. Drug Metab Dispos. 1999;27(1):21–5.PubMedGoogle Scholar
  119. 119.
    Grene-Lerouge NAM, Bazin-Redureau MI, Debray M, Scherrmann JMG. Interspecies scaling of clearance and volume of distribution for digoxin-specific Fab. Toxicol Appl Pharmacol. 1996;138(1):84–9.PubMedGoogle Scholar
  120. 120.
    Mahmood I. Interspecies scaling of protein drugs: prediction of clearance from animals to humans. J Pharm Sci. 2004;93(1):177–85.PubMedGoogle Scholar
  121. 121.
    Chen T, Mager DE, Kagan L. Interspecies modeling and prediction of human exenatide pharmacokinetics. Pharm Res. 2013;30(3):751–60.PubMedCentralPubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  1. 1.Pharmacokinetics, Dynamics and MetabolismPfizer Inc.GrotonUSA

Personalised recommendations