Studies of the Metabolism of Asialotransferrins: The Mechanism for the Hypercatabolism of Human Asialotransferrin in the Rabbit

1974 ◽  
Vol 52 (7) ◽  
pp. 645-651 ◽  
Author(s):  
E. Regoeczi ◽  
M. W. C. Hatton
Keyword(s):  
Sialic Acid ◽  
Plasma Protein ◽  
Half Life ◽  
Hepatic Clearance ◽  
The Other ◽  
Human Transferrin ◽  
Human Control ◽  
Clearance Mechanism ◽  
Catabolic Process

The behavior in vivo of human asialotransferrin in rabbits was studied in such a manner as to permit a comparison of this catabolic process with the generalized hepatic clearance mechanism for asialoglycoproteins described by Ashwell and Morell.Progressive desialylation of human transferrin in the range 50–100% yielded transferrin molecules with circulation times inversely proportional to the loss of sialic acid. The shape of plasma protein-bound radioactivity curves indicated that treatment of transferrin with neuraminidase resulted in at least two types of asialo derivatives. The biological half-life of one of them was close to 60% of that of control transferrin and the other one disappeared from the plasma with a half-life of approximately 1.5–2.5 h. Oxidation of over 50% of the terminal galactosyl groups in human asialotransferrin prolonged the circulation time of asialotransferrin.Assays of tissue radioactivities following mixed injection of human control and asialotransferrins showed that the two proteins possessed the same affinity for lung, kidney, and spleen, but asialotransferrin was preferentially taken up by the liver.On the basis of these observations, it seems likely that the mechanism which has been claimed as a generalized pathway for the clearance of asialoglycoproteins is also responsible for the rapid elimination of heterologous human asialotransferrin in the rabbit.

Hepatocytes Ingest Longterm Refrigerated Platelets: A Novel Platelet Clearance Mechanism.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1523-1523 ◽  
Author(s):  
Viktoria Rumjantseva ◽  
Emma C. Josefsson ◽  
Hans Wandall ◽  
John H. Hartwig ◽  
Thomas P. Stossel ◽  
...  
Keyword(s):  
Cold Storage ◽  
Fluorescent Microscopy ◽  
Hepatic Clearance ◽  
Human Platelets ◽  
Lectin Domain ◽  
Clearance Mechanism ◽  
Rapid Clearance

Abstract We previously reported that the lectin domain of αMβ2 receptors on hepatic macrophages mediates rapid clearance of washed murine platelets transfused after refrigeration for 2 hours, recognizing exposed βN-acetylglucosamine (βGlcNAc) residues of N-linked glycans on clustered platelet GPIbα molecules and that the same receptors elicit phagocytosis of refrigerated human platelets human macrophages in vitro. A platelet-associated galactosyltransferase catalyzes the covering of βGlcNAc residues with galactose in the presence of UDP-galactose, thereby blocking clearance of cold mouse platelets in vivo and phagocytosis of human platelets in vitro. These intriguing findings contradicted earlier evidence that refrigeration of human platelets procured for transfusion only promotes their rapid clearance after prolonged (>8h) incubation and also are inconsistent with the well-known recognition system for exposed galactose residues through asialoglycoprotein (ASGP) receptors. Reconciling these contradictions, we report that the absence of plasma during storage accounts for the differences in time of exposure to cold to promote clearance and that mouse platelets cold-stored in plasma also only clear rapidly after long-term (48h) storage. We also found that hepatic clearance of long-term cold-stored (LTCS) mouse platelets occurs in hepatocytes. Streptavidin-POD staining revealed abundant LTCS biotinylated platelets in hepatocyte phagosomes. Furthermore, cells of the hepatocyte HepG2 line avidly ingest fluorescently-labeled LTCS human platelets (7-fold above the baseline of room-temperature-stored platelets), as evidenced by flow cytometry, fluorescent microscopy and by time-laps video microscopy. Long-term cold storage increases by ~1.7-fold platelet binding of the galactose-specific lectin RCA I, implying that with long-term cold storage, exposed galactose residues cluster sufficiently to induce recognition by hepatocyte ASGPR receptors. The results define a new clearance mechanism, representing the first example of blood cell removal by a non-myeloid cell. Since we find that human platelets also express a cell surface sialotransferase that adds sialic acid to galactose residues, we suggest that a combination of sialylation and glactosylation, achievable by addition of sugar substrates alone, might accommodate long-term cold storage of platelets for transfusion.

scholarly journals Carbohydrate PEGylation, an approach to improve pharmacological potency

2014 ◽  
Vol 10 ◽  
pp. 1433-1444 ◽  
Author(s):  
M Eugenia Giorgi ◽  
Rosalía Agusti ◽  
Rosa M de Lederkremer
Keyword(s):  
Molecular Weight ◽  
Polyethylene Glycol ◽  
Sialic Acid ◽  
Half Life ◽  
Viral Infections ◽  
Carbohydrate Moiety ◽  
Covalent Attachment ◽  
Low Molecular Weight ◽  
Pharmacokinetic Properties

Conjugation with polyethylene glycol (PEG), known as PEGylation, has been widely used to improve the bioavailability of proteins and low molecular weight drugs. The covalent conjugation of PEG to the carbohydrate moiety of a protein has been mainly used to enhance the pharmacokinetic properties of the attached protein while yielding a more defined product. Thus, glycoPEGylation was successfully applied to the introduction of a PEGylated sialic acid to a preexisting or enzymatically linked glycan in a protein. Carbohydrates are now recognized as playing an important role in host–pathogen interactions in protozoal, bacterial and viral infections and are consequently candidates for chemotherapy. The short in vivo half-life of low molecular weight glycans hampered their use but methods for the covalent attachment of PEG have been less exploited. In this review, information on the preparation and application of PEG-carbohydrates, in particular multiarm PEGylation, is presented.

Prediction of In Vivo Hepatic Clearance and Half-Life of Drug Candidates in Human Using Chimeric Mice with Humanized Liver

2011 ◽  
Vol 40 (2) ◽  
pp. 322-328 ◽  
Author(s):  
Seigo Sanoh ◽  
Aya Horiguchi ◽  
Kazumi Sugihara ◽  
Yaichiro Kotake ◽  
Yoshitaka Tayama ◽  
...  
Keyword(s):  
Half Life ◽  
Hepatic Clearance ◽  
Chimeric Mice ◽  
Drug Candidates

Differential regional metabolism of glucagon in anesthetized pigs

2003 ◽  
Vol 285 (3) ◽  
pp. E552-E560 ◽  
Author(s):  
Carolyn F. Deacon ◽  
Mette Kelstrup ◽  
Ramona Trebbien ◽  
Letty Klarskov ◽  
Mette Olesen ◽  
...  
Keyword(s):  
Half Life ◽  
The Other ◽  
Metabolic Clearance ◽  
Main Site ◽  
Dpp Iv ◽  
C And N ◽  
Glucagon Immunoreactivity ◽  
Plasma Half Life ◽  
Regional Metabolism

Glucagon metabolism under basal (endogenous) conditions and during intravenous glucagon infusion was studied in anesthetized pigs by use of midregion (M), COOH-terminal (C), and NH2-terminal (N)-RIAs. Arteriovenous concentration differences revealed a negative extraction of endogenous glucagon immunoreactivity across the portal bed (-35.4 ± 11.0, -40.3 ± 9.6, -35.6 ± 16.9%, M-, C-, N-RIA, respectively), reflecting net secretion of pancreatic glucagon and intestinal glicentin and oxyntomodulin, but under exogenous conditions, a net extraction occurred (11.6 ± 3.6 and 18.6 ± 5.7%, C- and N-RIA, respectively). Hindlimb extraction of endogenous (17.4 ± 3.7%, C-RIA) and exogenous (29.1 ± 4.8 and 19.8 ± 5.1%, C- and M-RIA) glucagon was detected, indicating M and C cleavage of the molecule. Renal extraction of glucagon was detected by all assays under endogenous (19.4 ± 6.7, 33.9 ± 7.1, 29.5 ± 6.7%, M-, C-, N-RIA) and exogenous conditions (46.9 ± 4.8, 46.4 ± 6.0, 47.0 ± 7.7%; M-, C-, N-RIA), indicating substantial elimination of the peptide. Hepatic glucagon extraction was undetectable under basal conditions and detected only by M-RIA (10.0 ± 3.8%) during glucagon infusion, indicating limited midregional cleavage of the molecule. The plasma half-life determined by C- and N-RIAs (2.7 ± 0.2 and 2.3 ± 0.2 min) were similar, but both were shorter than when determined by M-RIA (3.2 ± 0.2 min, P < 0.02). Metabolic clearance rates were similar regardless of assay (14.4 ± 1.1, 13.6 ± 1.7, 17.0 ± 1.7 ml·kg-1·min-1, M-, C-, N-RIA). Porcine plasma degraded glucagon, but this was not significantly affected by the dipeptidyl peptidase IV (DPP IV) inhibitor valine-pyrrolidide, and in anesthetized pigs, glucagon's metabolic stability was unchanged by DPP IV inhibition. We conclude that tissue-specific metabolism of glucagon occurs, with the kidney being the main site of removal and the liver playing little, if any, role. Furthermore, valine-pyrrolidide has no effect on glucagon stability, suggesting that DPP IV is unimportant in glucagon metabolism in vivo, in contrast to its significant role in the metabolism of the other proglucagon-derived peptides and glucose-dependent insulinotropic polypeptide.

In Vivo and In Vitro Comparison of Various Factor VIII Concentrates

1977 ◽  
Author(s):  
I.M. Nilsson ◽  
U. Hedner
Keyword(s):  
Factor Viii ◽  
Half Life ◽  
The Other ◽  
Crossed Immunoelectrophoresis ◽  
Factor Viii Concentrates ◽  
Fibrinogen Content ◽  
In Vivo Recovery ◽  
In Vitro Comparison

Five different factor VIII concentrates, AHF-Kabi(=fraction 1-0), Krynativ-Kabi(=cryoprecipitate), Hemofil-Hyland, AHF-Profilate-Abbott, Kryobulin-Immuno, available in Sweden for treatment of haemophiliacs were compared with respect to in vivo recovery of F VIII:C and survival time and in vitro properties. The parameters studied were F VIII:C, F VIIIR:AG, crossed Immunoelectrophoresis, F VIII:Rcof, fibrinogen content and F XIII activity. All the preparations had higher values for F VIIIR:AG than for F VIII:C. The quotient was highest for Hemofil, Krynativ-Kabi and Kryobulin and varied between 4 and 7. The lowest quotient, 1.3 to 4, showed AHF-Kabi. The units of F VIII:Rcof were almost the same as the units of F VIII:C. AHF-Kabi had the highest fibrinogen content and was the only preparation with high amounts of F XIII. In cross Immunoelectrophoresis AHF-Kabi showed a similar pattern to that of normal plasma. The other preparation had a different pattern suggesting less hetero-genicity of the molecule. The in vivo recovery was about the same for all the concentrates but AHF-Kabi had a significantly longer half-life (18-26 hrs); the corresponding figures for Hemofil were 8-16 hrs when given to the same patients. Only AHF-Kabi was able to completely normalize the defect in von Willebrand’s disease.

A Critical Role for N- and O-Linked Carbohydrates In Modulating Von Willebrand Factor Clearance In Vivo

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 382-382 ◽  
Author(s):  
Emily McRae ◽  
Orla Rawley ◽  
Hendrik Nel ◽  
Rachel Therese McGrath ◽  
Gudmundur Bergsson ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Half Life ◽  
Conflicts Of Interest ◽  
Lectin Binding ◽  
Critical Role ◽  
Gel Filtration ◽  
Macrophage Depletion ◽  
Plasma Half Life

Abstract Abstract 382FN2 VWF is a multimeric plasma sialoglycoprotein essential for normal haemostasis. Although the biosynthesis, structure and functional properties of VWF have been well characterized, the molecular mechanism(s) underlying its clearance remain poorly understood. Nevertheless, enhanced VWF clearance is important in the pathophysiology of VWD. Moreover, emerging data suggest that variation in VWF glycosylation (notably ABO blood group) may constitute an important regulator of in vivo clearance rates. To define the role of VWF glycans in modulating clearance, VWF was purified from human plasma (pdVWF) by cryoprecipitation and gel filtration. Subsequently, VWF glycosylation was modified using exoglycosidases and quantified by specific lectin-binding ELISAs. Finally, the effect of altered glycosylation on VWF plasma half-life was characterized by administration of VWF glycan variants to VWF−/− mice. Wild type pdVWF was cleared in biphasic manner, characterized by a rapid initial phase followed by a slower secondary phase (t1/2 = 46.9 min). Enzymatic desialylation of VWF with α2–3,6,8,9 neuraminidase (Neu-VWF) markedly enhanced VWF clearance (t1/2 = 3.7 min; p<0.01). Digestion of pdVWF with α2–3 neuraminidase to remove predominantly O-linked sialic acid (which constitutes less than 20% total VWF sialylation) was also sufficient to markedly enhance VWF clearance (t1/2 = 13.1 min; p<0.05). In the presence of the asialoglycoprotein receptor (ASGPR)-antagonist ASOR, the mean residence time of Neu-VWF was identical to that of pd-VWF. Recent studies have shown that macrophages may be important in VWF clearance. Since the ASGPR is expressed on both hepatocytes and macrophages, the effect of macrophage depletion on VWF clearance was assessed. Pre-treatment with liposome-encapsulated clodronate depleted F4/80+CD11b+ murine macrophages by 75%, and significantly prolonged Neu-VWF survival. However Neu-VWF survival was not corrected to that observed in the presence of ASOR. For example, plasma Neu-VWF survival after 5 mins was corrected from 30±6% to 92±7% in the presence of ASOR, compared to 78±10% following clodronate macrophage-depletion. Cumulatively, these findings demonstrate that both N- and O-linked sialylation are critical in protecting VWF against ASGPR-mediated clearance. Moreover, ASGPR-modulated clearance is at least in part macrophage-dependent. ß-galactose residues exposed following removal of capping sialic acid are recognised by the ASGPR. To further define the role of specific sugars in regulating VWF clearance, the effect of terminal sialic acid and sub-terminal galactose removal by sequential neuraminidase and galactosidase digestions was studied. Surprisingly, VWF exposed to sequential neuraminidase and galactosidase digestions (NeuGal-VWF) was cleared rapidly from the plasma in a monophasic fashion (t1/2 = 4.8 min). Moreover, treatment with PNGase F to completely remove N-linked carbohydrate structures also markedly decreased the plasma half-life (PNG-VWF; t1/2 = 2.1 min). In keeping with their lack of exposed galactose residues, the enhanced clearance of NeuGal-VWF and PNG-VWF were not mediated via the ASGPR (ASOR had no significant effect). In contrast, macrophage depletion by liposomal clodronate significantly inhibited the enhanced clearance of both NeuGal-VWF and PNG-VWF respectively. These data suggest that the ASGPR is not the only macrophage receptor involved in modulating VWF clearance, which is consistent with the relatively minor prolongation in VWF survival previously reported in Asgpr1−/− mice. These novel data demonstrate that variation in the N- or O-linked carbohydrate structures significantly modulate VWF half-life in vivo. Moreover, VWF clearance is not mediated solely through the ASGPR, but may also require additional as yet unidentified macrophage receptors for full clearance. Therefore, qualitative and quantitative variation in VWF glycosylation represents a key regulator of VWF clearance, and as such is likely to be of direct pathophysiological significance. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of paragloboside-like lipooligosaccharides may be a necessary component of gonococcal pathogenesis in men.

1991 ◽  
Vol 174 (6) ◽  
pp. 1601-1605 ◽  
Author(s):  
H Schneider ◽  
J M Griffiss ◽  
J W Boslego ◽  
P J Hitchcock ◽  
K M Zahos ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Cell Membrane ◽  
Neisseria Gonorrhoeae ◽  
Molecular Mass ◽  
Human Cell ◽  
Signs And Symptoms ◽  
The Other ◽  
Medical Attention ◽  
Phase Variations

To learn how lipooligosaccharide (LOS) phase variations affect pathogenesis, we studied two male volunteers who were challenged intraurethrally with Neisseria gonorrhoeae that make a single LOS of 3,600 daltons and sequentially followed LOS expression by gonococci as urethritis developed. LOS variation occurred in vivo. Signs and symptoms of gonorrhea began with the appearance of variants making 4,700-dalton LOS that are immunochemically similar to glycosphingolipids of human hematopoietic cells (Mandrell, R.E., J.M. Griffiss, and B.A. Macher. 1989. J. Exp. Med. 168:107) and that have acceptors for sialic acid. A variant that appeared at the onset of leukorrhoea was shed by 34/36 men with naturally acquired gonorrhea at the time they sought medical attention; the other two shed the variant associated with dysuria. None shed the challenge variant. These data show that in vivo phase shifts to higher molecular mass LOS that mimic human cell membrane glycolipids are associated with the development of gonococcal leukorrhea.

Comparative Analysis of Infused “Static”, Ex Vivo-Generated Platelets Vs. Infused Megakaryocytes-Generated Platelets: A Cautionary Tale

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2881-2881
Author(s):  
Yuhuan Wang ◽  
Vincent Hayes ◽  
Danuta Jarocha ◽  
Mortimer Poncz
Keyword(s):  
Stem Cells ◽  
Size Distribution ◽  
Half Life ◽  
Ex Vivo ◽  
The Other ◽  
Human Donor ◽  
Nsg Mice ◽  
Other Hand

Abstract Ex vivo-generated (EV) platelets beginning with embryonic stem cells or induced pluripotent stem cells (iPSCs) or hematopoietic progenitors cells (HPCs) may have clinical utility over donor-derived platelets, and efforts to produce such EV-platelets have been pursued in several laboratories under static megakaryocyte (Meg) culture conditions. Success in generating these has been reported, even demonstrating EV-platelet incorporation into growing thrombi in murine models. We have pursued an alternative strategy for thrombopoiesis using EV-Megs, grown from either human adult HPCs or from iPSCs or fetal livers, and directly infusing them into NOD-SCID gamma-interferon-deficient (NSG) mice. These studies were based on our prior observation that infused murine EV-Megs into wildtype mice are entrapped in the pulmonary bed and over the subsequent 1-4 hours release a wave of functional platelets at a significant level. We now show that infusion of human EV-Megs do the same in NSG mice, but resulting in two different pools of derived platelets: (1) A pool of young (as determined by thiazole orange staining) platelets having the same bell-shaped size distribution was seen as after infusion of human donor-derived platelets in these mice. These platelets take several hours to appear, but then have the same half-life as donor-derived platelets. These platelets are derived from the infused EV-Megs and were termed in vivo-generated (IV)-platelets. (2) A second pool of mostly older platelets was present that originated during the static growth of the EV-Megs, and these EV-platelets varied widely in size and age. Initially, these platelets accounted for a third of all the human platelets seen. Unlike IV-platelets, EV-platelets are immediately present and circulate with a markedly short half-life of 2-3 hours unless the recipient NSG mice were pre-treated with clodronate-ladened liposomes to delete their macrophage pools. Rapid removal of EV-platelets by macrophages is due to their being preactivated as determined by surface P-selectin expression in whole mice blood. These EV-platelets also had very limited further responsiveness to convulxin activation. On the other hand, human IV-platelets were quiescent prior to agonist stimulation in whole mice blood and responded strongly to agonist, similar to human donor-derived platelets infused into NSG mice. The IV-platelets were also selectively incorporated into cremaster arteriole laser injury thrombi over EV-platelets. Finally, directly harvested “platelets” from EV static-grown Megs were isolated and analyzed both in vitro and in vivo. Only a third of these particles are CD41+/CD42+ platelets and approximately half are actually CD41-/CD42-. Both pools showed the same wide size distribution in vitro and in vivo after infusion into mice. The CD41+/CD42+ fraction behaved just as the EV-platelets, but the CD41-/CD42- fraction half-life was unaffected by pre-treatment with clodronate-ladened liposomes. In summary, infused human Megs grown under static growth conditions released platelets in a recipient mouse’s lung with features characteristic of donor-derived platelets. On the other hand, “platelets” harvested from the same Megs were predominantly not even platelets as measured using CD41/CD42 markers. The portion that were CD41+/CD42+ platelets were preactivated, poorly responsive to agonists, and cleared rapidly. These findings set a standard on how to judge the potential clinical value of platelets derived from EV-Megs and also raise concerns whether direct visual imaging of “platelet release” in static culture is biologically meaningful given that most particles released were not CD41+/CD42+ platelets, and the ones that were CD41+/CD42+ were mis-sized and functionally limited. Disclosures No relevant conflicts of interest to declare.

scholarly journals Improved Pharmacokinetic Profile for BAY 81-8973 Due to Increased Branching and Sialylation of N-Linked Glycans of Recombinant Factor VIII

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1209-1209
Author(s):  
John M. Teare ◽  
David S. Kates ◽  
Anita Shah ◽  
Stephen Garger
Keyword(s):  
Single Dose ◽  
Sialic Acid ◽  
Factor Viii ◽  
Half Life ◽  
High Performance ◽  
Hemophilia A ◽  
Phase 1 ◽  
Hepatic Clearance ◽  
Pharmacokinetic Profile ◽  
Recombinant Factor Viii

Abstract The circulatory half-life of recombinant factor VIII (rFVIII) products is affected by glycosylation of the FVIII protein, including N-linked glycan branching and terminal sialic acid occupancy, primarily through receptor-mediated hepatic clearance (eg, asialoglycoprotein receptor [ASGPR] and lipoprotein receptor-related protein [LRP]). BAY 81-8973 (Kovaltry®, Bayer, Berkeley, CA) is an unmodified full-length rFVIII for treatment of hemophilia A. The BAY 81-8973 manufacturing process results in a product of enhanced purity with a consistently high degree of branching and sialylation of N-linked glycans. This study evaluated whether a relationship exists between N-linked glycosylation patterns and pharmacokinetic (PK) characteristics of BAY 81-8973 and 2 other rFVIII products (sucrose-formulated rFVIII [rFVIII-FS; Kogenate® FS, Bayer] and antihemophilic factor (recombinant) plasma/albumin-free method [rAHF-PFM; Advate®, Shire, Westlake Village, CA]). N-linked glycans or terminal carbohydrates were enzymatically removed from immobilized BAY 81-8973, rFVIII-FS, and rAHF-PFM proteins and analyzed using high-performance liquid chromatography to determine the percentage of individual N-linked glycan structures and degree of sialylation of each structure. PK data were available from 2 separate phase 1 crossover studies in which the PK profile of BAY 81-8973 was compared with that of rFVIII-FS (n=26) and rAHF-PFM (n=18) in patients with severe hemophilia A who received a single 50-IU/kg dose of each product. BAY 81-8973 and rFVIII-FS had increased N-linked glycan branching with higher levels of sialylation compared with rAHF-PFM. Levels of trisialylated glycans were 29.0% for BAY 81-8973 versus 11.5% for rFVIII-FS and 4.8% to 5.5% for rAHF-PFM; tetrasialylated glycans were 12.0% versus 2.8% and 0.6%, respectively. Degree of sialylation was 96% for BAY 81-8973, 94% for rFVIII-FS, and 78% to 81% for rAHF-PFM. Based on chromogenic assay results from the single-dose phase 1 PK studies, BAY 81-8973 half-life was 15% longer than that for rFVIII-FS and 16% longer than rAHF-PFM. Increases in the percentage of sialylated tri-antennary and tetra-antennary N-glycans correlated well with longer half-life of rFVIII in humans (adjusted R2=0.978 and 0.892 for tri-antennary and tetra-antennary N-glycans, respectively). Higher percentages of sialylation (ie, sialic acid capping) correlated with a longer half-life (adjusted R2=0.697), but the relationship was not as strong as that between glycan branching and half-life. Improved PK for BAY 81-8973 relative to rFVIII-FS and rAHF-PFM as seen in single-dose crossover PK studies might be related to this greater level of branching and sialylation, which may prolong the time BAY 81-8973 remains in the circulation. Disclosures Teare: Bayer: Employment. Kates:Bayer: Employment. Shah:Bayer: Employment. Garger:Bayer: Employment.

Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

1977 ◽  
Vol 16 (04) ◽  
pp. 157-162 ◽  
Author(s):  
C. Schümichen ◽  
B. Mackenbrock ◽  
G. Hoffmann
Keyword(s):  
Normal Saline ◽  
Half Life ◽  
Compound A ◽  
Short Half Life ◽  
Low Concentrations ◽  
The Stability ◽  
Kinetics Of ◽  
In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

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