Heparin Metabolism: Isolation and Characterization of Uroheparin

Mcallister, Bruce M.; Demis, D. Joseph

doi:10.1038/212293a0

Cited by 37 publications

(7 citation statements)

References 8 publications

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“…46 Bound heparin is internalized and depolymerized ( Fig 4 ). 47,48 The slower nonsaturable mechanism of clearance is largely renal. At therapeutic doses, a large proportion of heparin is cleared through the rapid saturable, dose-dependent mechanism.…”

Section: Structure and Mechanism Of Actionmentioning

confidence: 99%

Parenteral Anticoagulants

García

Baglin

Weitz

et al. 2012

Chest

893

480

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This article describes the pharmacology of approved parenteral anticoagulants. These include the indirect anticoagulants, unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and danaparoid, as well as the direct thrombin inhibitors hirudin, bivalirudin, and argatroban. UFH is a heterogeneous mixture of glycosaminoglycans that bind to antithrombin via a unique pentasaccharide sequence and catalyze the inactivation of thrombin, factor Xa, and other clotting enzymes. Heparin also binds to cells and plasma proteins other than antithrombin causing unpredictable pharmacokinetic and pharmacodynamic properties and triggering nonhemorrhagic side effects, such as heparin-induced thrombocytopenia (HIT) and osteoporosis. LMWHs have greater inhibitory activity against factor Xa than thrombin and exhibit less binding to cells and plasma proteins than heparin. Consequently, LMWH preparations have more predictable pharmacokinetic and pharmacodynamic properties, have a longer half-life than heparin, and are associated with a lower risk of nonhemorrhagic side effects. LMWHs can be administered once daily or bid by subcutaneous injection, without coagulation monitoring. Based on their greater convenience, LMWHs have replaced UFH for many clinical indications. Fondaparinux, a synthetic pentasaccharide, catalyzes the inhibition of factor Xa, but not thrombin, in an antithrombin-dependent fashion. Fondaparinux binds only to antithrombin. Therefore, fondaparinux-associated HIT or osteoporosis is unlikely to occur. Fondaparinux exhibits complete bioavailability when administered subcutaneously, has a longer half-life than LMWHs, and is given once daily by subcutaneous injection in fixed doses, without coagulation monitoring. Three additional parenteral direct thrombin inhibitors and danaparoid are approved as alternatives to heparin in patients with HIT.

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Section: Structure and Mechanism Of Actionmentioning

confidence: 99%

Parenteral Anticoagulants

García

Baglin

Weitz

et al. 2012

Chest

893

480

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show abstract

“…Both LMWH and LHD were not metabolised by the liver microsomes because they do not contain desulphamidase. Usually, heparin is partially degraded in the liver and partially eliminated by the kidneys in the form that retains biological activity (47). It has also been reported that around 10% of glycosaminoglycans with anti-FXa activity are recoverable in the urine of healthy volunteers who have been subcutaneously given prophylactic doses of LMWH (48).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic evaluation of an oral tablet form of low-molecular-weight heparin and deoxycholic acid conjugate as a novel oral anticoagulant

Park¹,

Jeon²,

Kim³

et al. 2011

Thromb Haemost

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This study was designed to develop a solid oral dosage form of deoxycholic acid (DOCA)-conjugated low-molecular-weight heparin (LMWH) and to evaluate its oral absorption, distribution, and metabolic stability for the prospect of providing an orally bioavailable LMWH. The LMWH derivative (LHD) was synthesised and then formulated with solubilisers and other pharmaceutical excipients to form a solid tablet. Its absorption and distribution after oral administration were evaluated in mice, rats, and monkeys. The in vitro metabolic stability of LHD was examined by liver microsome assays. More than 80% of LHD was released from the tablet within 60 minutes, guaranteeing rapid tablet disintegration after oral administration. Oral bioavailability of LHD in mice, rats and monkeys were 16.1 ± 3.0, 15.6 ± 6.1, and 15.8 ± 2.5%, respectively. After the oral administration of 131I-tyramine-LHD, most of the absorbed drug remained in the blood circulation and was eliminated mainly through the kidneys. LHD was hardly metabolised by the liver microsomes and showed a stable metabolic pattern similar to that of LMWH. In a rat thrombosis model, 10 mg/kg of orally administered LHD reduced thrombus formation by 60.8%, which was comparable to the anti-thrombotic effect of the subcutaneously injected LMWH (100 IU/kg). Solid tablets of LHD exhibited high oral absorption and statistically significant therapeutic effects in preventing venous thromboembolism. Accordingly, LHD tablets are expected to satisfy the unmet medical need for an oral heparin-based anticoagulant as an alternative to injectable heparin and oral warfarin.

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“…The half life of UFH is not only very variable due to its earlier described heterogeneity , but also due to its two‐phased and dose‐dependent elimination (the half‐life increases with increasing dose) . The rapid, saturable elimination phase is thought to reflect UFH binding to vascular endothelial cells, macrophages and reticuloendothelial cells , where it is internalized, depolymerized and metabolized into smaller and less sulphated forms . The slower phase corresponds to renal clearance.…”

Section: Biophysical and Pharmacokinetic Propertiesmentioning

confidence: 99%

Initial anticoagulation in patients with pulmonary embolism: thrombolysis, unfractionated heparin, LMWH, fondaparinux, or DOACs?

Leentjens

Peters

Esselink

et al. 2017

Brit J Clinical Pharma

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The initial treatment of haemodynamically stable patients with pulmonary embolism (PE) has dramatically changed since the introduction of low molecular weight heparins (LMWHs). With the recent discovery of the direct oral anticoagulant drugs (DOACs), initial treatment of PE will be simplified even further. In several large clinical trials it has been demonstrated that DOACs are not inferior to standard therapy for the initial treatment of PE, and because of their practicability they are becoming the agents of first choice. However, many relative contraindications to DOACs were exclusion criteria in the clinical trials. Therefore, LMWHs will continue to play an important role in initial PE treatment and in some cases there still is a role for unfractionated heparin (UFH). In this review we will give an overview of the biophysical, pharmacokinetic and pharmacodynamic properties of anticoagulants currently available for the initial management of PE. In addition, we will provide a comprehensive overview of the indications for the use of UFH, LMWHs and DOACs in the initial management of PE from a pharmacokinetic/-dynamic point of view.

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Heparin Metabolism: Isolation and Characterization of Uroheparin

Cited by 37 publications

References 8 publications

Parenteral Anticoagulants

Parenteral Anticoagulants

Pharmacokinetic evaluation of an oral tablet form of low-molecular-weight heparin and deoxycholic acid conjugate as a novel oral anticoagulant

Initial anticoagulation in patients with pulmonary embolism: thrombolysis, unfractionated heparin, LMWH, fondaparinux, or DOACs?

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