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

Abstract

INTRODUCTION:

MC710 is a mixture agent consisting of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a weight ratio of 1:10 developed as a novel bypassing agent for the management of the bleeding of hemophilia patients with inhibitors. The pharmacokinetics, distribution, and excretion of (125)I-labeled-FVIIa ((125)I-FVIIa) and -FX ((125)I-FX) were studied in male rats after a single intravenous administration of (125)I-FVIIa or (125)I-FX combined with MC710.

METHODS:

(125)I-FVIIa or (125)I-FX was administered intravenously with MC710 to male rats in a single dosage (FVIIa 0.4 mg and FX 4 mg/kg body weight) and radioactivity and antigen levels in plasma were quantified for 24h. Urine and feces were sampled to study the excretion of radioactivity during 168 h after dosing. Whole-body autoradiography was performed to evaluate the qualitative distribution of radioactivity 168 h after dosing.

RESULTS AND CONCLUSIONS:

The half-life (t(1/2)α and t(1/2)β) of radioactivity and FVIIa antigen were 0.704 and 6.27 h, and 0.496 and 1.66 h, respectively and the area under the plasma concentration-time curve (AUC(0-∞)) of radioactivity and FVIIa antigen were 17,932 and 8671 ng·h/mL, respectively. The t(1/2) of radioactivity and FX antigen were 4.06 and 3.05 h, respectively, and the AUC(0-∞) of radioactivity and FX antigen were 320,143 and 395,794 ng·h/mL, respectively. About 80% of the administered dose of radioactivity was excreted in urine and feces by 168 h after administration. Tissue distribution experiments showed that FVIIa- and FX-related (125)I accumulated in bone and bone marrow, and disappeared slowly.

• Authors: Yasushi Nakatomi, Manami Tsuji, Teruhisa Nakashima, Soutaro Gokudan, Hiroki Miyazaki, Kazuhiko Tomokiyo, Yoichi Ogata, Satomi Harano, Hajime Matsui, Takamichi Shigaki, Takahiro Nakamura, Masayuki Mogi
• Journal: Thrombosis research (Thromb Res) Vol. 129 Issue 1 Pg. 62-7 (Jan 2012) ISSN: 1879-2472 [Electronic] United States
• PMID: 21621824 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier Ltd. All rights reserved.

Chemical References

• Coagulants
• Drug Combinations
• Iodine Radioisotopes
• MC710
• Factor X
• Factor VIIa

Topics

• Animals
• Area Under Curve
• Bone Marrow (metabolism)
• Bone and Bones (metabolism)
• Coagulants (administration & dosage, blood, pharmacokinetics, urine)
• Drug Combinations
• Enzyme-Linked Immunosorbent Assay
• Factor VIIa (administration & dosage, pharmacokinetics, pharmacology, urine)
• Factor X (administration & dosage, pharmacokinetics, urine)
• Feces (chemistry)
• Half-Life
• Humans
• Injections, Intravenous
• Iodine Radioisotopes
• Male
• Rats
• Tissue Distribution