Movement of Heparins Across Rat Gastric Mucosa is Dependent on Molecular Weight and pH

Moazed, Banafsheh; Hiebert, Linda M.

doi:10.1007/s11095-008-9751-8

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…This suggests that UFH may be best absorbed in the stomach, while LMWH may be best absorbed in the intestine where a much larger absorptive surface is available and LMWH may be absorbed faster or more completely. 22 Thus, the present studies indicate that orally administered heparins, both UFH and LMWH, are effective antithrombotic agents in both rat arterial and venous models and can be given in repetitive doses without bleeding. Oral administration produces a similar antithrombotic effect as seen with subcutaneous administration, supporting the notion that orally administered heparins are readily absorbed.…”

Section: Discussionmentioning

confidence: 52%

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Repeated Doses of Oral and Subcutaneous Heparins Have Similar Antithrombotic Effects in a Rat Carotid Arterial Model of Thrombosis

Hiebert

Ping

Wice

2011

J Cardiovasc Pharmacol Ther

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Although heparins are usually injected intravenously or subcutaneously, antithrombotic activity is observed in rat models following single oral heparin doses. Since repetitive dosing is usually needed for thromboprophylaxis, study objectives were to determine whether repetitive oral heparin prevented arterial thrombosis and to compare effectiveness to subcutaneous administration. Wistar rats were given subcutaneous or oral unfractionated heparin ([UFH] 1 mg/kg per 48 h), low-molecular-weight heparin ([LMWH] tinzaparin, 0.1 mg/kg per 12 h), or saline for 30 days. On the last day, thrombosis was initiated by placing 30% FeCl(3)-soaked filter paper on the distal carotid. Subsequent flow measurements, for a 60-minute period, included recorded time of initial thrombus formation (time till thrombus begins [TTB]), and time until carotid occlusion (time till occlusion [TTO]). The formed thrombus was dried and weighed. The activated partial thromboplastin time (aPTT), anti-factor Xa, and antithrombin activity were determined from the plasma. Both oral and subcutaneous heparins significantly increased TTB and TTO. Time of initial thrombus formations were 12.6 ± 1.1, 21.2 ± 2.2, 25.3 ± 3.9, 21.7 ± 3.1, and 21.3 ± 1.7 minutes and TTOs were 29.3 ± 3.6, 54.8 ± 4.0, 60.0 ± 0.3, 56.7 ± 3.3, and 58.3 ± 1.7 minutes (mean ± SEM) for control, subcutaneous UFH, oral UFH, subcutaneous LMWH, and oral LMWH, respectively. Thrombus weight was 2.52 ± 0.29 g in control and was reduced to 43%, 23%, 33%, and 28% of control weight for subcutaneous UFH, oral UFH, subcutaneous LMWH, and oral LMWH, respectively. Thrombus weight was significantly less for oral compared to subcutaneous UFH. The aPTT for oral UFH, and anti-factor Xa activity in the LMWH-treated groups were significantly greater than control (two-tailed t tests). These findings confirm that orally administered heparins are absorbed. Repeated treatment with oral heparin showed similar antithrombotic activity compared to subcutaneous heparin. Oral heparin use for arterial thromboprophylaxis should be further investigated.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Repeated Doses of Oral and Subcutaneous Heparins Have Similar Antithrombotic Effects in a Rat Carotid Arterial Model of Thrombosis

Hiebert

Ping

Wice

2011

J Cardiovasc Pharmacol Ther

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“…There are several lines of evidence supporting the possibility of oral absorption of heparin. Hiebert et al (39,40) demonstrated that heparin could be permeated through the gastric mucosal membrane, and the repeated dose of oral UFH could show sufficient antithrombotic effects similar to subcutaneous administration. However, due to its hydrophilicity and negative charge density, heparin has limited intestinal membrane permeability.…”

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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Oral fondaparinux: use of lipid nanocapsules as nanocarriers and in vivo pharmacokinetic study

Ramadan¹,

Lagarce²,

Tessier-Marteau³

et al. 2011

IJN

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Abstract:Oral anticoagulant therapy could be advanced using lipid-based nanoparticulate systems. This study examined lipid nanocapsules for their oral absorption potential as the first step in developing oral fondaparinux (Fp) novel carriers. Using phase inversion method and cationic surfactants such as hexadecyltrimethyl ammonium bromide (CTAB) or stearylamine (SA), cationic lipid nanocapsules (cLNCs), loaded with Fp on their surface, were prepared and characterized (zeta potential, size and Fp association efficiency and content). In vivo studies were conducted after single oral increasing doses of Fp-loaded cLNCs (0.5 to 5 mg/kg of Fp) in rats and the concentration of Fp in the plasma was measured by anti-factor Xa activity assay. The monodisperse, (∼50 nm), positively charged Fp-cLNCs with high drug loadings demonstrated linear pharmacokinetic profiles of the drug with an increased oral absolute bioavailability (up to ∼21%) compatible with therapeutic anticoagulant effect (.0.2 µg/mL).

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Movement of Heparins Across Rat Gastric Mucosa is Dependent on Molecular Weight and pH

Abstract: Decreasing heparin size, increases movement through gastric mucosa at mucosal buffer pH 7.4 but not pH 4.0. The stomach environment may favor UFH absorption while the intestine environment favors LMWH absorption.

Cited by 5 publications

References 26 publications

Repeated Doses of Oral and Subcutaneous Heparins Have Similar Antithrombotic Effects in a Rat Carotid Arterial Model of Thrombosis

Repeated Doses of Oral and Subcutaneous Heparins Have Similar Antithrombotic Effects in a Rat Carotid Arterial Model of Thrombosis

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

Oral fondaparinux: use of lipid nanocapsules as nanocarriers and in vivo pharmacokinetic study

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