Pharmacokinetic investigations of the α-human thrombin-hirudin complex in rhesus monkeys

Grötsch, H.; Hropot, M.; Berscheid, G.; Crause, Peter; Malerczyk, V.; Apidopoulos, G.; Haun, G.; Hušák, Brigitte

doi:10.1016/0049-3848(92)90198-j

Cited by 4 publications

(6 citation statements)

References 8 publications

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“…It is important to note that in rhesus monkeys that received a bolus of lepirudin, renal clearance also contributed ≈50% to plasma clearance. 18 These results are similar to those obtained in this study. The method of administration of the labeled lepirudin did not affect the extravascular clearance (Table 2).…”

Section: Discussionsupporting

confidence: 95%

“…Similar results were obtained when clearance was calculated from the radioactive radioactive count rates ( Table 2). This value is not very different from that determined in rhesus monkeys, 18 but differs greatly from the results reported for humans, rats, rabbits, and dogs. 6,15 Labeled lepirudin, infused over 30 min, was cleared by the kidneys at a significantly higher rate than that administered as a bolus (Table 2).…”

Section: Discussioncontrasting

confidence: 69%

“…It has been speculated that the remainder may be catabolized by the kidneys and that the methods used to determine lepirudin are unable to recognize the degradation products. 6,14,18,19 The quantification of the percentage labeled lepirudin found in the bladder argues against renal catabolisation. If the labeled lepirudin was catabolized, much more than 50 to 60% of administered labeled lepirudin would have been detected in the bladder at the end of the study.…”

Section: Discussionmentioning

confidence: 99%

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Sites of elimination and pharmacokinetics of recombinant [131I]lepirudin in baboons

Meiring

Badenhorst

et al. 1999

Journal of Pharmaceutical Sciences

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Lepirudin has a short half-life, and only 50-60% of the intravenously administered dose is excreted by the kidneys. The fate of the remainder is unknown. We designed a study to determine the fate of this lepirudin. In each of six baboons, [131I]lepirudin was given intravenously as a bolus or infused over 30 min, 24 h apart. The in vivo redistribution of [131I]lepirudin was determined and quantified by scintillation camera imaging. In all studies, the half-life of [131I]lepirudin, as determined from the disappearance of radioactivity, was 21 +/- 3 min. The half-life determined from the disappearance of lepirudin, measured by the Ecarin Clotting Time (ECT) method, was similar at 23 +/- 8 min. Results obtained with the labeled lepirudin are therefore comparable with those obtained using the plasma concentration of lepirudin. When lepirudin was administered as a bolus, the half-life was 18 +/- 4 min, and lepirudin was cleared from the plasma at a rate of 42 +/- 12 mL/min and by the kidneys at 23 +/- 2 mL/min. Following infusion over 30 min, the half-life and total and renal clearances were not significantly different. In both studies, between 50 and 60% of the administered lepirudin was excreted by the kidney. Studies on sacrificed baboons showed that appreciable amounts of lepirudin were present in the bile, indicating the liver as a contributor to the elimination of lepirudin.

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Section: Discussionsupporting

confidence: 95%

Section: Discussioncontrasting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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Sites of elimination and pharmacokinetics of recombinant [131I]lepirudin in baboons

Meiring

Badenhorst

et al. 1999

Journal of Pharmaceutical Sciences

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“…The plasma clearance of radioactivity from co-injected *I-DLT-labelled thrombin-hirudin complexes was nearly identical, no matter which component of the complex was labelled with *I-DLT, and plasma radioactivity was completely acetone-precipitable at all time points. As previously observed in monkeys [26], the complexes were eliminated from plasma more slowly than hirudin itself. For comparison, the clearance curves for *I-DLT-thrombin-AT and *I-DLThirudin are also shown.…”

Section: Immunoprecipitation Studiessupporting

confidence: 79%

Catabolism of hirudin and thrombin-hirudin complexes in the rat

Bichler

Baynes

Thorpe

1993

Biochemical Journal

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The metabolic fate of the anticoagulant protein, hirudin, and its complex with thrombin are presently unknown. Therefore we have labelled hirudin and human thrombin-hirudin complex with the residualizing label dilactitol-125I-tyramine (*I-DLT) in order to identify their tissue sites of catabolism in the rat. The rapid plasma clearance of hirudin after intravenous injection was unaffected by *I-DLT labelling, and by 2 h 6% or less of the injected dose remained in the blood. The majority (80.3 +/- 4.0%, n = 2) of *I-DLT-hirudin radioactivity recovered in tissues was found in kidney, and kidney was also at least 150 times more active in taking up hirudin, on a weight basis, than any other tissue examined (liver, spleen, skin, muscle, intestine, fat, lung). *I-DLT-hirudin which bound to thrombin was isolated by chromatography on concanavalin A-Sepharose; hirudin itself does not bind to concanavalin A. Radioactivity from thrombin-*I-DLT-hirudin was precipitable by anti-thrombin antibody and *I-DLT-thrombin-hirudin was precipitable by anti-hirudin antibody. By 1 h after injection of labelled thrombin-hirudin complexes, the recoveries of radioactivity from hirudin and thrombin in liver were comparable (38.6 +/- 3.0 and 36.4 +/- 4.1%, n = 3), whereas more radioactivity was recovered in kidney from hirudin than from thrombin (27.6 +/- 8.7 compared with 13.6 +/- 4.5%) and less was recovered in lung (0.4 +/- 0.2 compared with 17.7 +/- 2.9%). We conclude that hirudin is catabolized predominantly in kidney, whereas the thrombin-hirudin complex is catabolized by both liver and kidney.

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“…Although r-hi rudin plasma half-life is rather short anyway [2,3,[12][13][14], removal from circulation can be significantly accelerated by hemodialysis [6], Since glomerular filtration is the major excre- tion route under normal conditions in man and other species [2,13,[15][16][17][18][19][20], nondiagnosed renal impairment depicts another po tential risk of anticoagulant accumulation. Termination of r-hirudin application and he mofiltration should quickly overcome bleed ing tendency [21].…”

Section: Discussionmentioning

confidence: 99%

Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

Diehl

Römisch²,

Hein³

et al. 1995

Pathophysiol Haemos Thromb

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The specific thrombin inhibitor r-hirudin (HBW 023) has been demonstrated to be effective in preventing thrombosis in preclinical models. Up to now, no bleeding complications have been observed using therapeutically effective doses in animal studies. However, in case of inadvertent overdosing the occurrence of undesired impairment of coagulation cannot be excluded. As a potential antidote an activated prothrombin complex concentrate (APC) was tested on its ability to normalize blood coagulation. APC given as bolus injections 5 min after termination of 1-hour r-hirudin infusions of 0.1, 0.3, 1.0 and 3.0 mg/kg neutralized the r-hirudin-induced prolongation of whole blood coagulation time in rabbits completely within 5 min without any clot formation in the blood vessels or capillaries of the heart, kidneys, or lungs. Furthermore, bleeding time prolongation induced by bolus application of 3.0 and 30.0 mg/kg r-hirudin was significantly inhibited by APC within 5 min. These results suggest that administration of APC may be an effective way to reverse the effects of r-hirudin in the coagulation system in case of inadvertent overdosing of r-hirudin.

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Pharmacokinetic investigations of the α-human thrombin-hirudin complex in rhesus monkeys

Cited by 4 publications

References 8 publications

Sites of elimination and pharmacokinetics of recombinant [131I]lepirudin in baboons

Sites of elimination and pharmacokinetics of recombinant [131I]lepirudin in baboons

Catabolism of hirudin and thrombin-hirudin complexes in the rat

Investigation of Activated Prothrombin Complex Concentrate as Potential Hirudin Antidote in Animal Models

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