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Pharmacokinetics and Metabolism of Cardiovascular Therapeutic Proteins

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Protein Pharmacokinetics and Metabolism

Part of the book series: Pharmaceutical Biotechnology ((PBIO,volume 1))

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Abstract

The blood coagulation pathway consists of a series of inactive and active enzymes (Fig. 1). In certain individuals, some of the elements, or factors, of this cascade may be inoperative or have reduced activity, and in some cases may be missing. Such cases give rise to the bleeding disorder hemophilia. There are three categories of patients with the deficiency: patients with normal amounts of factor that has reduced clotting activity; patients with factor and activity equally reduced; patients in whom the factor and its activity are undetectable. The existence of at least two forms of hemophilia was suggested by the results of experiments performed by Pavlovsky (1947) in which the mixing of the blood of two patients classified as hemophilics caused a correction of the clotting times of each blood sample. The more common hemophilia A, or classical hemophilia, and hemophilia B, or Christmas disease, occur as a result of factor VIII (FVIII) and factor IX (FIX) deficiency, respectively. These two diseases are X-linked recessive traits in which males are affected. Patients with severe hemophilia A or B have undetectable (less than 1% of normal) concentrations of FVIII or FIX and suffer from recurrent

Simplified scheme depicting the relationship of the intrinsic and extrinsic coagulation pathways and the fibrinolysis pathway. Roman numerals refer to individual coagulation factors, and tPA, UK, SK, and APSAC refer to tissue plasminogen activator, urokinase, streptokinase, and anisoylated plasminogen streptokinase activator complex, respectively.

spontaneous hemarthroses and retroperitoneal bleeding. A related disorder is von Willebrand’s disease which is caused by a lack of von Willebrand’s factor (and also FVIII). von Willebrand’s factor is essential for platelet aggregation. Other recognized hemophilias result from deficiencies in factors V, VII, X, XI, and XIII.

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References

  • Aggeler, P. M., 1961, Physiological basis for transfusion therapy in hemorrhagic disorders, Transfusion 1:71–74.

    PubMed  CAS  Google Scholar 

  • Allain, J. P., 1984, Principles of in vivo recovery and survival studies, Scand. J. Haematol 33(Suppl. 40):161–165.

    Google Scholar 

  • Astrup, T., and Permin, P. M., 1947, Fibrinolysis in animal organism, Nature 159:681–682.

    PubMed  CAS  Google Scholar 

  • Bakhit, C., Lewis, D., Billings, R., and Malfroy, B., 1987, Cellular catabolism of recombinant tissue-type plasminogen activator, J. Biol. Chem. 262:8716–8720.

    PubMed  CAS  Google Scholar 

  • Barrowcliffe, T. W., Stableforth, R., and Dormandy, K. M., 1973, Small scale preparation and clinical use of factor IX prothrombin complex, Vox Sang. 25:426–441.

    PubMed  CAS  Google Scholar 

  • Baughman R. A., 1987, Pharmacokinetics of tissue plasminogen activator, in: Tissue Plasminogen Activator in Thrombolytic Therapy (B. E. Sobel, D. Collen, and E. B. Grossbard, eds.), Dekker, New York, pp. 41–53.

    Google Scholar 

  • Been, M., deBono, D. P., Muir, A. L., Boulton, F. E., Fears, R., Standring, R., and Ferres, H., 1986, Clinical effects and kinetic properties of intravenous anistre-plase-anisoylated plasminogen-streptokinase activator complex (BRL26921) in acute myocardial infarction, Int. J. Cardiol. 11:53–61.

    PubMed  CAS  Google Scholar 

  • Bertina, R. M., and Veltkamp, J. J., 1981, Physiology and biochemistry of factor IX, in: Haemostasis and Thrombosis (A. L. Bloom and D. P. Thomas, eds.), Churchill Livingstone, Edinburgh, pp. 98–110.

    Google Scholar 

  • Bidwell, E., Booth, J. M., Dike, G. W. R., and Denson, K. W. E., 1967, The preparation for therapeutic use of a concentrate of factor IX containing also factors II, VII and X, Br. J. Haematol. 13:586–590.

    Google Scholar 

  • Biggs, R., and Denson, K. W. E., 1963, The fate of prothrombin and factors VII, IX and X transfused to patients deficient in these factors, Br. J. Haematol 9:532–547.

    PubMed  CAS  Google Scholar 

  • Binder, B. R., Spragg, J., and Austen, K. F., 1979, Purification and characterization of human vascular plasminogen activator derived from blood vessel perfusates, J. Biol Chem. 254:1998–2003.

    PubMed  CAS  Google Scholar 

  • Bloom, A. L., 1990, Physiology of blood coagulation, Haemostasis 20(Suppl.): 14–29.

    PubMed  CAS  Google Scholar 

  • Brinkhous, K. M., Hedner, U., Garris, J. B., Diness, V., and Read, M. S., 1989, Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease, Proc. Natl Acad. Sci. USA 86:1382–1386.

    PubMed  CAS  Google Scholar 

  • Broze, G. J., and Majerus, P. W., 1980, Purification and properties of human coagulation factor VII, J. Biol. Chem. 255:1242–1247.

    PubMed  CAS  Google Scholar 

  • Broze, G. J., and Miletich, J. P., 1987, Characterization of the inhibition of tissue factor in serum, Blood 69:150–155.

    PubMed  Google Scholar 

  • Carson, S. D., 1987, Tissue factor (coagulation factor III) inhibition by apolipoprotein A-II, J. Biol Chem. 262:718–721.

    PubMed  CAS  Google Scholar 

  • Chavin, S. I., and Weidner, S. M., 1984, Blood clotting factor IX. Loss of activity after cleavage of sialic acid residues, J. Biol Chem. 259:3387–3390.

    PubMed  CAS  Google Scholar 

  • Christensen, L. R., and MacLeod, C. M., 1945, Proteolytic enzyme of serum: Characterization, activation, and reaction with inhibitors, J. Gen. Physiol. 28:559–583.

    PubMed  CAS  Google Scholar 

  • Col, J. J., Col-DeBeys, S. M., Renkin, J. P., LaVenne-Pardonge, E. M., Bachy, J. L., and Morian, M. H., 1989, Pharmacokinetics, thrombolytic efficacy and hemorrhagic risk of different streptokinase regimens in heparin-treated acute myocardial infarction, Am. J. Cardiol. 63:1185–1192.

    PubMed  CAS  Google Scholar 

  • Collen, D., Stassen, J. M., Marafino, B. J., Builder, S., DeCock, F., Ogez, J., Tajiri, D., Pennica, D., Bennett, W. F., Salwa, J., and Hoyng, C. F., 1984, Biological properties of human tissue-type plasminogen activator obtained by expression of recombinant DNA in mammalian cells, J. Pharmacol. Exp. Ther. 231:146–152.

    PubMed  CAS  Google Scholar 

  • Collen, D., Zamarron, C., Lijnen, H. R., and Hoylaerts, M., 1986, Activation of plasminogen pro-urokinase. II. Kinetics, J. Biol. Chem. 261:1259–1266.

    PubMed  CAS  Google Scholar 

  • Cossum, P., Littlewood, J., Ferraiolo, B., Green, J., and Bunting, S., 1990, Recombinant human tissue factor (rhTF) pharmacokinetics and effects in normal and hemophiliac dogs, Pharm. Res. 7(Suppl.):S-45 (abstract).

    Google Scholar 

  • Daly, H. M., and Haddon, M. E., 1988, Clinical experience with a pasteurized human plasma concentrate in factor XIII deficiency, Thromb. Haemostas. 59:171–174.

    CAS  Google Scholar 

  • Eaton, D., Rodriguez, H., and Vehar, G. A., 1986, Proteolytic processing of human factor VIII. Correlation of specific cleavages by thrombin, factor Xa, and activated protein C with activation and inactivation of factor VIII coagulant activity, Biochemistry 25:505–512.

    PubMed  CAS  Google Scholar 

  • Esmail, A. F., Dupe, R. J., English, P. D., and Smith, R. A. G., 1984, Pharmacokinetic and pharmacodynamic comparison of acylated streptokinase plasminogen complexes with different deacylation rate constant, Haemostasis 14: 84.

    Google Scholar 

  • Fear, J. D., Miloszewski, K. J. A., and Losowsky, M. S., 1983, The half-life of factor XIII in the management of inherited deficiency, Thromb. Haemostas. 49:102–105.

    CAS  Google Scholar 

  • Fears, R., Ferres, H., and Standring, R., 1987, The protective effect of acylation on the stability of anisoylated plasminogen streptokinase activator complex in human plasma, Drugs 33(Suppl. 3):57–63.

    PubMed  CAS  Google Scholar 

  • Ferres, H., Hibbs, M., and Smith, R. A. G., 1987, Deacylation studies in vitro on anisoylated plasminogen streptokinase activator complex, Drugs 33(Suppl. 3):80–82.

    PubMed  CAS  Google Scholar 

  • Fisher, K. L., Gorman, C., Vehar, G., O’Brien, D. P., and Lawn, R. M., 1987, Cloning and expression of tissue factor cDNA, Thromb. Res. 48:89–99.

    PubMed  CAS  Google Scholar 

  • Fletcher, A. D., Alkjaersig, N., and Sherry, S., 1959, The clearance of heterologous protein from the circulation of normal and immunized man, J. Clin. Invest. 37:1306–1315.

    Google Scholar 

  • Fong, K.-L., and Lynn, R. K., 1986, Disposition and metabolism of tissue-type plasminogen activator (tPA) in the isolate perfused rat liver, Pharmacologist 28: 117.

    Google Scholar 

  • Fong, K.-L., Crysler, C. S., Mico, B. A., Boyle, K. E., Kopia, G. A., Kopaciewicz, L., and Lynn, R. K., 1988, Dose-dependent pharmacokinetics of recombinant tissue-type plasminogen activator in anesthetized dogs following intravenous infusion, Drug Metab. Dispos. 16:201–206.

    PubMed  CAS  Google Scholar 

  • Fuchs, H. E., Trapp, H. G., Griffith, M. J., Roberts, H. R., and Pizzo, S. V., 1984, Regulation of factor IXa in vitro in human and mouse plasma and in vivo in the mouse, J. Clin. Invest. 73:1696–1703.

    PubMed  CAS  Google Scholar 

  • Fuchs, H. E., Berger, H., and Pizzo, S. V., 1985, Catabolism of human tissue plasminogen activator in mice, Blood 65:539–544.

    PubMed  CAS  Google Scholar 

  • Garabedian, H. D., Gold, H. K., Leinbacj, R. C., Johns, J. A., Yasuda, T., Kanke, M., and Collen, D., 1987, Comparative properties of two clinical preparations of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction, J. Am. Coll. Cardiol. 9:599–607.

    PubMed  CAS  Google Scholar 

  • Gemmill, J. D., Hogg, K. J., Burns, J. M., Rae, A. P., Dunn, F. G., Fears, R., Ferres, H., Standring, R., Greenwood, H., Pierce, D., and Hills, W. S., 1991, A comparison of the pharmacokinetic properties of streptokinase and anistreplase in acute myocardial infarction, Br. J. Clin. Pharmacol. 31:143–147.

    PubMed  CAS  Google Scholar 

  • Gill, F. M., 1984, The natural history of factor VIII inhibitors in patients with hemophilia A, Prog. Clin. Biol. Res. 150:19–24.

    PubMed  CAS  Google Scholar 

  • Girard, T. J., Warren, L. A., Novotny, W. F., Likert, K. M., Brown, S. G., Miletich, J. P., and Broze, G. J., 1989, Functional significance of the Kunitz-type inhibitory domains of lipoprotein-associated coagulation inhibitor. Nature 338: 518–520.

    PubMed  CAS  Google Scholar 

  • Gonmori, H., and Takeda, Y., 1975, Properties of canine tissue thromboplastin from brain, lung, arteries and veins, Am. J. Physiol. 229:618–626.

    PubMed  CAS  Google Scholar 

  • Goodnight, S. H., Britell, C. W., Wuepper, K. D., and Osterud, B., 1979, Circulating factor IX antigen-inhibitor complexes in hemophilia B following infusion of a factor IX concentrate, Blood 53:93–103.

    PubMed  Google Scholar 

  • Grierson, D. S., and Bjornsson, T. D., 1987, Pharmacokinetics of streptokinase in patients based on amidolytic activator complex activity, Clin. Pharmacol. Ther. 41:304–313.

    PubMed  CAS  Google Scholar 

  • Gunzler, W. A., Steffens, G. J., Otting, F., Kim, S. M., Frankus, E., and Rohe, L., 1982, The primary structure of high molecular mass urokinase from human urine. The complete amino acid sequence of the A chain, Hoppe-Seylers Z. Physiol Chem. 363:1155–1165.

    PubMed  CAS  Google Scholar 

  • Hedner, U., and Kisiel, W., 1983, Use of human factor VIIa in the treatment of two hemophilia A patients with high-titer inhibitors, J Clin. Invest. 71:1836–1841.

    PubMed  CAS  Google Scholar 

  • Hedner, U., Glazer, S., Pingel, K., Alberts, K. A., Blomback, M., Schulman, S., and Johnsson, H., 1988, Successful use of recombinant factor VIIa in patients with severe haemophilia A during synovectomy, Lancet 2: 1193.

    PubMed  CAS  Google Scholar 

  • Hellstern, P., Miyashita, C., Kohler, M., von Blohn, G., Kiehl, R., Biro, G., Schwerdt, H., and Wenzel, E., 1987, Measurement of factor VIII procoagulant antigen in normal subjects and in hemophilia A patients by an immunoradiometric assay and by an enzyme-linked immunosorbent assay, Haemostasis 17:173–181.

    PubMed  CAS  Google Scholar 

  • Hoag, M. S., Aggeler, P. M., and Powell, A. H., 1960, Disappearance rate of concentrated proconvertin extracts in congenital and acquired hypoconvertinemia, J. Clin. Invest. 39:554–563.

    PubMed  CAS  Google Scholar 

  • Hoag, M. S., Johnson, F. F., Robinson, J. A., and Aggeler, P. M., 1969, Treatment of hemophilia B with a new clotting-factor concentrate, N. Engl J. Med. 280:581–583.

    PubMed  CAS  Google Scholar 

  • Holvoet, P., Cleemput, H., and Collen, D., 1985, Assay of human tissue-type plasminogen activator (t-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA, Thromb. Haemostas. 54:684–687.

    CAS  Google Scholar 

  • Hotchkiss, A., Refino, C. J., Leonard, C. K., O’Connor, J. V., Crowley, C., McCabe, J., Tate, K., Nakamura, G., Powers, D., Levinson, A., Mohler, M., and Spellman, M., 1988, The influence of carbohydrate structure on the clearance of recombinant tissue-type plasminogen activator, Thromb. Haemostas. 60: 255–261.

    CAS  Google Scholar 

  • Ichinose, A., Fujikawa, K., and Suyama, T., 1986, The activation of prourokinase by plasma kallikrein and its inactivation by thrombin, J. Biol. Chem. 261: 3486–3489.

    PubMed  CAS  Google Scholar 

  • Jackson, K. W., and Tang, J., 1982, Complete amino acid sequence of streptokinase and its homology with serine proteases, Biochemistry 21:6620–6625.

    PubMed  CAS  Google Scholar 

  • Kadhom, N., Wolfrom, C., Gautier, M., Allain, J. P., and Frommel, D., 1988, Factor VIII procoagulant antigen in human tissues, Thromb. Haemostas. 59:289–294.

    CAS  Google Scholar 

  • Kjellman, H., 1984, Calculations of factor VIII in vivo recovery and half-life, Scand. J. Haematol. 33(Suppl. 40): 165–174.

    Google Scholar 

  • Kohler, M., Seifreid, E., Hellstern, P., Pindur, G., Miyashita, C., Morsdorf, S., Fasco, F., and Wenzel, E., 1988, In vivo recovery and half-life time of a steam-treated factor IX concentrate in hemophilia B patients, Blut 57:341–345.

    PubMed  CAS  Google Scholar 

  • Kohler, M., Hellstern, P., Pindur, G., Wenzel, E., and von Blohm, G., 1989, Factor VII half-life after transfusion of a steam-treated prothrombin complex concentrate in a patient with homozygous factor VII deficiency, Vox Sang. 56:200–201.

    PubMed  CAS  Google Scholar 

  • Kopia, G. A., Kopaciewicz, L. J., Fong, K.-L., Crysler, C. S., Boyle, K., and Ruffblo, R. R., 1988, Evaluation of the acute hemodynamic effects and pharmacokinetics of coronary thrombolysis produced by intravenous tissue-type plasminogen activator in the anesthetized dog, J. Cardiovasc. Pharmacol. 12:308–316.

    PubMed  CAS  Google Scholar 

  • Korninger, C., Stassen, J. M., and Collen, D., 1981, Turnover of human extrinsic (tissue-type) plasminogen activator in rabbits, Thromb. Haemostas. 46: 658–661.

    CAS  Google Scholar 

  • Kuiper, J., Otter, M., Rijken, D. C., and van Berkel, T. J. C., 1988, Characterization of the interaction in vivo of tissue-type plasminogen activator with liver cells, J. Biol. Chem. 263:18220–18224.

    PubMed  CAS  Google Scholar 

  • Kuzel, T., Green, D., Stulberg, S. D., and Baron, J., 1988, Arthropathy and surgery in congenital factor VII deficiency, Am. J. Med. 84:771–774.

    PubMed  CAS  Google Scholar 

  • Lewis, J. H., Bontempo, F. A., Spero, J. A., Ragni, M. V., and Starzi, T. E., 1985, Liver transplantation in a hemophiliac, N. Engl. J. Med. 312:1189–1192.

    PubMed  CAS  Google Scholar 

  • Littlewood, J. D., and Barrowcliffe, T. W., 1987, The development and characterization of antibodies to human factor VIII in haemophilic dogs, Thromb. Haemostas. 57:314–321.

    CAS  Google Scholar 

  • Loeliger, E. A., and Hensen, A., 1964, On the turnover of factors II, VII, IX, X under pathological conditions, Thromb. Diath. Haemorrh. 13(Suppl.):95.

    Google Scholar 

  • Loewy, A. G., Dahlberg, A., Dunathan, D., Kriel, R., and Wolfinger, H. L., 1961, Fibrinases. II. Some physical properties, J Biol. Chem. 236:2634–2643.

    PubMed  CAS  Google Scholar 

  • Longo, G., Matucci, M., Messori, A., Morfini, M., and Rossi-Ferrini, P., 1986, Pharmacokinetics of a new heat-treated concentrate of factor VIII estimated by model-independent methods, Thromb. Res. 42:471–476.

    PubMed  CAS  Google Scholar 

  • Longo, G., Cinotti, S., Filimberti, E., Giustarini, G., Messori, A., Morfini, M., and Rossi-Ferrini, P., 1987, Single-dose pharmacokinetics of factor IX evaluated by model-independent methods, Eur. J. Haematol. 39:426–433.

    PubMed  CAS  Google Scholar 

  • Markus, G., Evers, J. L., Hobika, J. H., 1976, Activator activities of the transient forms of the human plasminogen-streptokinase complex during its proteolytic conversion to the stable activator complex, J. Biol. Chem. 251:6495–6504.

    PubMed  CAS  Google Scholar 

  • McLellan, D. S., Pelly, C., McLellan, H. G., Jones, P., and Aronstam, A., 1982, The in vivo survival characteristics of factor VIII procoagulant antigen (VIILCAg) in haemophilia A subjects, Thromb. Res. 25:33–39.

    PubMed  CAS  Google Scholar 

  • Mariani, G., Mannucci, P. M., Mazzucconi, M. G., and Capitanio, A., 1978, Treatment of congenital factor VII deficiency with a new concentrate, Thromb. Haemostas. 39:675–682.

    CAS  Google Scholar 

  • Matucci, M., Messori, A., Donati-Cori, G., Longo, G., Vannini, S., Morfini, M., Tendi, E., and Rossi-Ferrini, P. L., 1985, Kinetic evaluation of four factor VIII concentrates by model-independent methods, Scand. J. Haematol. 34:22–28.

    PubMed  CAS  Google Scholar 

  • Messori, A., Longo, G., Matucci, M., Morfini, M., and Rossi-Ferrini, P. L., 1987, Clinical pharmacokinetics of factor VIII in patients with classic hemophilia, Clin. Pharmacokin. 13:365–380.

    CAS  Google Scholar 

  • Messori, A., Longo, G., Morfini, M., Cinotti, S., Filimberti, E., Giustarini, G., and Rossi-Ferrini, P., 1988, Multi-variate analysis of factors governing the pharmacokinetics of exogenous factor VIII in haemophiliacs, Eur. J. Clin. Pharmacol 35:663–668.

    PubMed  CAS  Google Scholar 

  • Mohler, M. A., Refino, C. J., Chen, S. A., Chen, A. B., and Hotchkiss, A. J., 1986, D-Phe-Pro-Arg-chloromethylketone: its potential use in inhibiting the formation of in vitro artifacts in blood collected during tissue-type plasminogen activator thrombolytic therapy, Thromb. Haemostas. 56:160–164.

    CAS  Google Scholar 

  • Morfini, M., Longo, G., Matucci, M., Vannini, S., Messori, A., Filimberti, E., Duminuco, M., Avanzi, G., and Rossi-Ferrini, P., 1984, Cryoprecipitate and factor VIII commercial concentrates: In vitro characteristics and in vivo compartmental analysis, Ric. Clin. Lab. 14:681–691.

    PubMed  CAS  Google Scholar 

  • Nilsson, I. M., Berntorp, E., and Zettervall, O., 1988, Induction of immune tolerance in patients with hemophilia and antibodies to factor VIII by combined treatment with intravenous IgG, cyclophosphamide and factor VIII, N. Engl. J. Med. 318:947–949.

    PubMed  CAS  Google Scholar 

  • Nilsson, I. M., Berntorp, E., Zettervall, O., and Dahlback, B., 1990, Noncoagulation inhibitory factor VIII antibodies after induction of tolerance to factor VIII in hemophilia A patients, Blood 75:378–383.

    PubMed  CAS  Google Scholar 

  • Nilsson, S., Wallen, P., and Mellbring, G., 1984, In vivo metabolism of human tissue-type plasminogen activator, Scand. J. Haematol 33:49–53.

    PubMed  CAS  Google Scholar 

  • Nilsson, S., Einarsson, M., Ekvarn, L., Haggroth, L., and Mattson, C., 1985, Turnover of tissue plasminogen activator in normal and hepatectomized rabbits, Thromb. Res. 39:511–521.

    PubMed  CAS  Google Scholar 

  • Noe, D. A., Bell, W. R., Ness, P. M., and Levin, J., 1986, Plasma clearance rates of coagulant factors VIII and IX in factor-deficient individuals, Blood 67:969–972.

    PubMed  CAS  Google Scholar 

  • Over, J., Sixma, J. J., Doucet-de Brune, M., Trieschnigg, M. M., Vlooswijk, R. A., Beeser-Visser, N. H., and Bouma, B. N., 1978, Survival of 125iodine-labelled factor VIII in normals and patients with classic hemophilia, J. Clin. Invest. 62:223–234.

    PubMed  CAS  Google Scholar 

  • Over, J., Sixma, J. J., Bouma, B. N., Bolhuis, P. A., Vlooswijk, R. A., and Beeser-Visser, N. H., 1981, Survival of iodine-125-labeled factor VIII in patients with von Willebrand’s disease, J Lab. Clin. Med. 97:332–344.

    PubMed  CAS  Google Scholar 

  • Owen, C. A., and Bowie, W. J., 1975, Infusion therapy in hemophilia A and B, in: Handbook of Hemophilia (K. M. Brinkhous and H. C. Hemker, eds.), Excerpta Medica, Amsterdam, pp. 449–463.

    Google Scholar 

  • Pannell, R., and Gurewich, V., 1986, Pro-urokinase: A study of its stability in plasma and of a mechanism for its selective fibrinolytic effect, Blood 67:1215–1223.

    PubMed  CAS  Google Scholar 

  • Pavlovsky, A., 1947, Contribution to the pathogenesis of hemophilia, Blood 2:185–191.

    PubMed  CAS  Google Scholar 

  • Pennica, D., Holmes, W. E., Kohr, W. J., Harkins, R. N., Vehar, G. A., Ward, C. A., Bennett, W. F., Yelverton, E., Seeburg, H. L., Heyneker, H. L., Goeddel, D. V., and Collen, D., 1983, Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli, Nature 301:214–221.

    PubMed  CAS  Google Scholar 

  • Pohl, G., Kalstrom, M., Bergsdorf, N., Wallen, P., and Jornvall, H., 1984, Tissue plasminogen activator: peptide analyses confirm an indirectly derived amino acid sequence; identify the active site serine residue, establish glycosylation sites and localize variant differences, Biochemistry 23:3701–3707.

    PubMed  CAS  Google Scholar 

  • Ranby, M., Bergesdorf, N., and Nilsson, T., 1989a, Enzymatic properties of the one-and two-chain form of tissue plasminogen activator, Thromb. Res. 27: 175–183.

    Google Scholar 

  • Ranby, M., Nguyen, G., Scarabin, P. Y., and Samama, M., 1989b, Immunoreactivity of tissue plasminogen activator and its inhibitor complexes: Biochemical and multicenter validation of a two-site immunosorbent assay, Thromb. Haemostas. 61: 409–414.

    CAS  Google Scholar 

  • Rao, L. V. M., Rapaport, S. L., and Bajaj, S. P., 1986, Activation of human factor VII in the initiation of tissue factor-dependent coagulation, Blood 68:685–691.

    PubMed  CAS  Google Scholar 

  • Ratnoff, O. D., 1986, Factor VIII concentrates, J. Am. Med. Assoc. 255:325–326.

    CAS  Google Scholar 

  • Reddy, K. N. N., 1976, Kinetics of active center formation in dog plasminogen by streptokinase and activity of a modified streptokinase, J. Biol. Chem. 251:3913–3920.

    Google Scholar 

  • Reddy, K. N. N., 1988, Streptokinase—Biochemistry and clinical application, Enzyme 40:79–89.

    PubMed  CAS  Google Scholar 

  • Rick, M. E., Popovsky, M. A., and Krizek, D. M., 1985, Degradation of factor VIII coagulant antigen by proteolytic enzymes, Br. J. Haematol 61:477–486.

    PubMed  CAS  Google Scholar 

  • Rijken, D. C., and Collen, D., 1981, Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture, J. Biol. Chem. 256:7035–7041.

    PubMed  CAS  Google Scholar 

  • Rijken, D. C., Wijngaards, G., Zaal-DeJong, M., and Welbergen, J., 1979, Purification and partial characterization of plasminogen activator from human uterine tissue, Biochim. Biophys. Acta 580: 140.

    PubMed  CAS  Google Scholar 

  • Rijken, D. C., Hoylaerts, M., and Collen, D., 1982, Fibrinolytic properties of one-chain and two-chain human extrinsic (tissue-type) plasminogen activator, J. Biol Chem. 257:2920–2925.

    PubMed  CAS  Google Scholar 

  • Rock, G. A., Cruickshank, W. H., Tackaberry, E. S., Ganz, P. R., and Palmer, D. S., 1983, Stability of VIII:C in plasma: The dependence on protease activity and calcium, Thromb. Res. 29:521–535.

    PubMed  CAS  Google Scholar 

  • Rodeghiero, F., Tosetto, A., DiBona, E., and Castaman, G., 1991, Clinical pharmaco-kinetics of a placenta-derived factor XIII concentrate in type I and type II factor XIII deficiency, Am. J. Hematol. 36:30–34.

    PubMed  CAS  Google Scholar 

  • Rousell, R. H., Kasper, C. K., and Schwartz, R. S., 1989, The pharmacology of a new pasteurized antihemophilic factor concentrate derived from human blood plasma, Transfusion 29:208–212.

    PubMed  CAS  Google Scholar 

  • Sandset, P. M., Warn-Cramer, B. J., Rao, L. V., Maki, S. L., and Rapaport, S. I., 1991, Depletion of extrinsic pathway inhibitor (EPI) sensitizes rabbits to disseminated intravascular coagulation induced with tissue factor: Evidence supporting a physiologic role for EPI as a natural anticoagulant, Proc. Natl. Acad. Sci. USA 88:708–712.

    PubMed  CAS  Google Scholar 

  • Schleef, R. R., Wagner, N. V., Sinha, M., and Loskutoff, D. J., 1986, A monoclonal antibody that does not recognize tissue-type plasminogen activator bound to its naturally occurring inhibitor, Thromb. Haemostas. 56:328–332.

    CAS  Google Scholar 

  • Schneider, C. L., 1947, The active principle of placental toxin: thromboplastin; its inactivator in blood: antithromboplastin, Am. J. Physiol 149:123–129.

    PubMed  CAS  Google Scholar 

  • Schwartz, R. S., Abildgaard, C. F., Aledort, L. M., Arkin, S., Bloom, A. L., Brackmann, H. H., Brettler, D. R., Fukui, H., Hilgartner, M. W., Inwood, M. J., Kasper, C. K., Kernoff, P. B., Levine, P. H., Lusher, J. M., Mannucci, P. M., Scharrer, I., MacKenzie, M. A., Pancham, N., Kuo, H. S., and Allred, R. U., 1990, Human recombinant DNA-derived antihemophilic factor (factor VIII) in the treatment of hemophilia A, N. Engl. J. Med. 323:1800–1805.

    PubMed  CAS  Google Scholar 

  • Seligsohn, U., Kasper, C. K., Osterud, B., and Rapaport, S. L. 1979, Activated factor VII: Presence in factor IX concentrates and persistence in the circulation after infusion, Blood 53:828–837.

    PubMed  CAS  Google Scholar 

  • Siefried, E., and Tanswell, P., 1987, Comparison of specific antibody, D-Phe-Pro-Arg-chloromethylketone and aprotinin for prevention of in vitro effects of recombinant tissue-type plasminogen activator on haemostasis parameters, Thromb. Haemostas. 58:921–926.

    Google Scholar 

  • Siefried, E., Tanswell, P., Rijken, D. C., Barrett-Bergshoeff, M. M., Su, C. A., and Kluft, C., 1988, Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers, Arzneim. Forsch. 38:418–422.

    Google Scholar 

  • Siefried, E., Tanswell, P., Ellbruck, D., Haerer, W., and Schmidt, A., 1989, Pharmacokinetics and haemostatic status during consecutive infusion of recombinant tissue-type plasminogen activator in patients with acute myocardial infarction, Thromb. Haemostas. 61:497–501.

    Google Scholar 

  • Siefring, G. E., and Castellino, F. J., 1976, Interaction of streptokinase with plasminogen: Isolation and characterization of a streptokinase degradation product, J. Biol. Chem. 257:3913–3920.

    Google Scholar 

  • Smedsrod, B., Einarsson, M., and Pertoft, H., 1988, Tissue plasminogen activator is endocytosed by mannose and galactose receptors of rat liver cells, Thromb. Haemostas. 59:480–484.

    CAS  Google Scholar 

  • Smith, K. J., and Thompson, A. R., 1981, Labeled factor IX kinetics in patients with hemophilia-B, Blood 58:625–629.

    PubMed  CAS  Google Scholar 

  • Standring, R., Fears, R., and Ferres, H., 1988, The protective effect of acylation on the stability of APSAC (Eminase) in human plasma, Fibrinolysis 2:157–163.

    CAS  Google Scholar 

  • Staniforth, D. H., Smith, R. A. G., and Hibbs, M., 1983, Streptokinase and anisoylated streptokinase plasminogen complex—Their action on haemostasis in human volunteers, Eur. J. Clin. Pharmacol. 24:751–756.

    PubMed  CAS  Google Scholar 

  • Steffens, G. J., Gunzler, W. A., Otting, F., Frankus, E., and Flohe, L., 1982, The complete amino acid sequence of low molecular mass urokinase from human urine, Hoppe-Seylers Z. Physiol. Chem. 363:1043–1058.

    PubMed  CAS  Google Scholar 

  • Stern, D. M., Drillings, M., Nossel, H. L., Hurlet-Jensen, A., LaGamma, K., and Owen, J., 1983, Binding of factors IX and IXa to cultured vascular endothelial cells, Proc. Natl. Acad. Sci. USA 80:4119–4123.

    PubMed  CAS  Google Scholar 

  • Stern, D. M., Knitter, G., Kisiel, W., and Nawroth, P. P., 1987, In vivo evidence of intravascular binding sites for coagulation factor IX, Br. J. Haematol. 66:227–232.

    PubMed  CAS  Google Scholar 

  • Stump, D. C., Thienpont, M., and Collen, D., 1986a, Urokinase-related proteins in human urine. Isolation and characterization of single-chain urokinase (prourokinase) and urokinase-inhibitor complex, J. Biol. Chem. 261: 1267–1273.

    PubMed  CAS  Google Scholar 

  • Stump, D. C., Lijnen, H. R., and Collen, D., 1986b, Purification and characterization of single-chain urokinase-type plasminogen activator from human cell cultures, J. Biol. Chem. 261: 1274–1278.

    PubMed  CAS  Google Scholar 

  • Stump, D. C., Kieckens, L., De Cock, F., and Collen, D., 1987, Pharmacokinetics of single-chain forms of urokinase-type plasminogen activator, J. Pharmacol. Exp. Ther. 242:245–250.

    PubMed  CAS  Google Scholar 

  • Tanswell, P., Seifried, E., Su, P. C., Feuerer, W., and Rijken, D. C., 1989, Pharmacokinetics and systemic effects of tissue-type plasminogen activator in normal subjects, Clin. Pharmacol. Ther. 46:155–162.

    PubMed  CAS  Google Scholar 

  • Tanswell, P., Heinzel, G., Greischel, A., and Krause, J., 1990, Nonlinear pharmacokinetics of tissue-type plasminogen activator in three animal species and isolated perfused rat liver, J. Pharmacol. Exp. Ther. 255:318–324.

    PubMed  CAS  Google Scholar 

  • Tebbe, U., Tanswell, P., Seifried, E., Feuerer, W., Scholz, K. H., and Herrmann, K. S., 1989, Single-bolus injection of recombinant tissue-type plasminogen activator in acute myocardial infarction, Am. J. Cardiol. 64:448–453.

    PubMed  CAS  Google Scholar 

  • Thompson, A. R., Forrey, A. W., Gentry, P. A., Smith, K. J., and Harker, L. A., 1980, Human factor IX in animals: Kinetics from isolated, radiolabelled protein and platelet destruction following crude concentrate infusions, Br. J. Haematol. 45:329–342.

    PubMed  CAS  Google Scholar 

  • Toole, J. J., Knopf, J. L., Wozney, J. M., Sultzman, L. A., Buecker, J. L., Pittman, D. D., Kaufman, R. J., Brown, E., Shoemaker, C., Orr, E. C., Amphlett, G. W., Foster, W. B., Coe, M. L., Knutson, G. J., Foss, D. W., and Hewick, R. M., 1984, Molecular cloning of a cDNA encoding human antihemophilic factor, Nature 312:342–347.

    PubMed  CAS  Google Scholar 

  • Van der Werf, F., Vanhaecke, J., de Geest, H., Verstraete, M., and Collen, D., 1986, Coronary thrombolysis with recombinant single-chain urokinase-type plasminogen activator in patients with acute myocardial infarction, Circulation 74:1066–1070.

    PubMed  Google Scholar 

  • Van der Werf, F., Jang, I. K., and Collen, D., 1987, Thrombolysis with recombinant human single-chain urokinase-type plasminogen activator (rscu-PA): Dose-response in dogs with coronary artery thrombosis, J. Cardiovasc. Pharmacol. 9:91–93.

    PubMed  Google Scholar 

  • Verstraete, M., Bounameaux, H., de Cock, F., Van der Werf, F., and Collen, D., 1985, Pharmacokinetics and systemic fibrinolytic effects of recombinant human tissue-type plasminogen activator (rt-PA) in humans, J. Pharmacol. Exp. Ther. 235:506–512.

    PubMed  CAS  Google Scholar 

  • Wallen, P., Ranby, M., Bergsdorf, N., and Kok, P., 1981, Purification and characterization of tissue plasminogen activator: On the occurrence of two different forms and the enzymatic properties, in: Progress in Fibrinolysis, Volume 5 (J. P. Davidson, I. M. Nilsson, and B. Astedt, eds.), Churchill Livingstone, Edinburgh, pp. 16–23.

    Google Scholar 

  • White, G. C., McMillan, C. W., Kingdon, H. S., and Shoemaker, C. B., 1989, Use of recombinant antihemophilic factor in the treatment of two patients with classic hemophilia, Lancet 320:166–170.

    Google Scholar 

  • Williams, W. J., 1983, Life span of plasma coagulation factors, in: Hematology (W. J. Williams, ed.), McGraw-Hill, New York, pp. 1230–1237.

    Google Scholar 

  • Wion, K. L., Kelly, D., Summerfield, J. A., Tuddenham, E. G., and Lawn, R. M., 1985, Distribution of factor VIII mRNA and antigen in human liver and other tissues, Nature 311:126–129.

    Google Scholar 

  • Wood, W. I., Capon, D. J., Simonsen, C. C., Eaton, D. L., Gitschier, J., Keyt, B., Seeburg, P. H., Smith, D. H., Hollingshead, P., Wion, K. L., Delwart, E., Tuddenham, E. G., Vehar, G. A., and Lawn, R. M., 1984, Expression of active human factor VIII from recombinant DNA clones, Nature 312:330–337.

    PubMed  CAS  Google Scholar 

  • Working, P. K., and Cossum, P. A., 1991, Clinical and preclinical studies with recombinant human proteins: The effect of antibody production, in: Peptides, Peptoids and Proteins: Proceedings of the 5 th Pittsburgh Pharmacodynamics Conference (P. Gazonne, ed.), Harvey Wilkes Books, Cincinnati.

    Google Scholar 

  • Zauber, N. P., and Levin, J., 1977, Factor IX levels in patients with hemophilia B (Christmas disease) following transfusion with concentrates of factor IX or fresh frozen plasma (FFP), Medicine 56:213–224.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Research and Development, Emisphere Technologies, Hawthorne, New York, 10532, USA

    Paul A. Cossum

  2. Department of Preclinical Development, Isis Pharmaceuticals, Carlsbad, California, 92008, USA

    Robert A. Baughman Jr.

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  1. Paul A. Cossum
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  1. R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania, USA

    Bobbe L. Ferraiolo

  2. Genentech, Inc., South San Francisco, California, USA

    Marjorie A. Mohler

  3. Alkermes, Inc., Cambridge, Massachusetts, USA

    Carol A. Gloff

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Cossum, P.A., Baughman, R.A. (1992). Pharmacokinetics and Metabolism of Cardiovascular Therapeutic Proteins. In: Ferraiolo, B.L., Mohler, M.A., Gloff, C.A. (eds) Protein Pharmacokinetics and Metabolism. Pharmaceutical Biotechnology, vol 1. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-2329-5_6

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  • DOI: https://doi.org/10.1007/978-1-4899-2329-5_6

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