Pharmacokinetics, distribution, and excretion of 125I-labeled human plasma-derived-FVIIa and -FX with MC710 (FVIIa/FX mixture) in rats

Nakatomi, Yasushi; Tsuji, Masaaki; Nakashima, Teruhisa; Gokudan, Soutaro; Miyazaki, Hiroyuki; Tomokiyo, Kazuhiko; Ogata, Youichi; Harano, Satomi; Matsui, Hajime; Shigaki, Takamichi; Nakamura, Takahiro; Mogi, Masayuki

doi:10.1016/j.thromres.2011.04.013

Cited by 5 publications

(2 citation statements)

References 17 publications

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“…Similar to the study by Herzog et al [ 43 ] of rIX-FP in wild-type rats, there was a 125 I-FIX signal retention with EHL factor (rIX-FP), seemingly at the mineralized bone surface region. This has also been previously observed for other GLA domain-containing clotting factors, FVII and FX [ 44 ]. Previous work by Thomsen et al [ 45 ] has shown that fully γ-carboxylated Gla domain-containing proteins, including FVII and FIX, are retained in mineralized bone that contains collagen and hydroxyapatite [ 46 ].…”

Section: Discussionsupporting

confidence: 85%

Biodistribution of recombinant factor IX, extended half-life recombinant factor IX Fc fusion protein, and glycoPEGylated recombinant factor IX in hemophilia B mice

Flier

Hong

Zhan

et al. 2023

Blood Coagulation &Amp; Fibrinolysis

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Extended half-life recombinant FIX (rFIX) molecules have been generated to reduce the dosing burden and increase the protection of patients with hemophilia B. Clinical pharmacology studies with recombinant factor IX Fc fusion protein (rFIXFc) report a similar initial peak plasma recovery to that of rFIX, but with a larger volume of distribution. Although the pegylation of N9-GP results in a larger plasma recovery, there is a smaller volume of distribution, suggesting less extravasation of the latter drug. In this study, we set out to compare the biodistribution and tissue localization of rFIX, rFIXFc, and glycoPEGylated rFIX in a hemophilia B mouse model. Radiolabeled rFIX, rFIXFc, and rFIX-GP were employed in in vivo single-photon emission computed tomography imaging (SPECT/CT), microautoradiography (MARG), and histology to assess the distribution of FIX reagents over time. Immediately following injection, vascularized tissues demonstrated intense signal irrespective of FIX reagent. rFIX and rFIXFc were retained in joint and muscle areas through 5 half-lives, unlike rFIX-GP (assessed by SPECT). MARG and immunohistochemistry showed FIX agents localized at blood vessels among tissues, including liver, spleen, and kidney. Microautoradiographs, as well as fluorescent-labeled images of knee joint areas, demonstrated retention over time of FIX signal at the trabecular area of bone. Data indicate that rFIXFc is similar to rFIX in that it distributes outside the plasma compartment and is retained in certain tissues over time, while also retained at higher plasma levels. Overall, data suggest that Fc fusion does not impede the extravascular distribution of FIX.

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Section: Discussionsupporting

confidence: 85%

Biodistribution of recombinant factor IX, extended half-life recombinant factor IX Fc fusion protein, and glycoPEGylated recombinant factor IX in hemophilia B mice

Flier

Hong

Zhan

et al. 2023

Blood Coagulation &Amp; Fibrinolysis

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“…At best, all the data presented in this article are semiquantitative for the positive quantitation of the test articles being studied and most likely underestimate concentrations of rVIIa-FP, rVIIa, and the control albumin used. Interestingly, these investigators compare their QWBA data to QWBA data reported in an earlier publication that used 125 I-labeled human plasma-derived FV11a and -FX with MC710 in rats (Nakatomi et al 2012), and in that report the investigators also did not evaluate the extent of biodehalogenation. Those authors actually reported relatively high "radioactivity levels in the thyroid, … kidney, … stomach, … and intracystic urine…" and that "at 168 h , radioactivity persisted in the thyroid gland…".…”

Section: Applications For Metabolism Studymentioning

confidence: 99%

Autoradiography techniques and quantification of drug distribution

Solon¹

2015

Cell Tissue Res

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The use of radiolabeled drug compounds offers the most efficient way to quantify the amount of drug and/or drug-derived metabolites in biological samples. Autoradiography is a technique using X- ray film, phosphor imaging plates, beta imaging systems, or photo-nuclear emulsion to visualize molecules or fragments of molecules that have been radioactively labeled, and it has been used to quantify and localize drugs in tissues and cells for decades. Quantitative whole-body autoradiography or autoradioluminography (QWBA) using phosphor imaging technology has revolutionized the conduct of drug distribution studies by providing high resolution images of the spatial distribution and matching tissue concentrations of drug-related radioactivity throughout the body of laboratory animals. This provides tissue-specific pharmacokinetic (PK) compartmental analysis which has been useful in toxicology, pharmacology, and drug disposition/patterns, and to predict human exposure to drugs and metabolites, and also radioactivity, when a human radiolabeled drug study is necessary. Microautoradiography (MARG) is another autoradiographic technique that qualitatively resolves the localization of radiolabeled compounds to the cellular level in a histological preparation. There are several examples in the literature of investigators attempting to obtain drug concentration data from MARG samples; however, there are technical issues which make that problematic. These issues will be discussed. This review will present a synopsis of both techniques and examples of how they have been used for drug research in recent years.

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