Heparin metabolism

Subcutaneous administration leads to a peak heparin level 2 h after injection and an onset of anticoagulant effect within 1-2 h. Intravenous administration leads to an immediate peak heparin level with anticoagulant activity within 20-30 min. Heparin binds extensively to a number of plasma proteins. Its volume of distribution is 0.07lkg in adults. The pharmacokinetics of heparin is complex and incompletely understood. Heparin metabolism occurs primarily in the reticuloendothelial system by desulfation. The LMWH agents have longer half-lives than standard heparin. Heparin s elimination half-life increases disproportionately with increasing dose, indicating saturable kinetics. 

Another major site of peptide metabolism is the blood and especially blood serum and plasma. From an extensive compilation of peptide tm values (over 100 peptides, plus derivatized and cyclized analogues, D-amino acid stereoisomers, peptide bond isosteres, etc.), it appears that the differences between serum, heparinized plasma, and whole blood are fairly limited [161]. Interspecies differences are larger, particularly between humans and rats, with most human/rat t1/2 ratios ranging from 1 1 to 25 1 ... 

Medical devices may be assisted in their function by pharmacological, immunological or metabolic means, but as soon as these means are not any more ancillary with respect to the principal purpose of a product, the product becomes a medicinal product. The claims made for a product, in accordance with its method of action may, in this context, represent an important factor for its classification as MD or medicinal product. Examples of MDs incorporating a medicinal substance with ancillary action include catheters coated with heparin or an antibiotic, bone cements containing antibiotic and blood bags containing anticoagulant. ... 

Heparin is highly bound to plasma proteins and has a short elimination half-life of 1-5 hours depending on the dose. It is distributed to the reticuloendothelial system and metabolized in the liver to inactive metabolites. It does not cross the placental barrier, however there is a risk of heparin-induced maternal osteopenia if it is used throughout pregnancy. 

Heparin s action is terminated by uptake and metabolism by the reticuloendothelial system and liver and by renal excretion of the unchanged drug and its de-polymerized and desulfated metabolite. The relative proportion of administered drug that is excreted as unchanged heparin increases as the dose increases. Renal insufficiency reduces the rate of heparin clearance from the blood. 

Heparin is well absorbed after subcutaneous administration and is not effective orally, and metabolized mainly in liver. It is not secreted in milk and does not cross placental barrier. 

LMWH have higher bioavailability after subcutaneous injection than standard, heparin. LMWH binds less than heparin to plasma proteins. The clearance of LMWH is mainly renal, independent of dose and slower than metabolic clearance of heparin. 

Metabolically Unstable Pharmacologically Active (Heparin Mimics)... 

While esters of sulfuric acid do not play as central a role in metabolism as do phosphate esters, they occur widely. Both oxygen esters (R-0-S03 , often referred to as O-sulfates) and derivatives of sulfamic acid (R-NH-SOg, N-suIfates) are found, the latter occurring in mucopolysaccharides such as heparin. Sulfate esters of mucopolysaccharides and of steroids are ubiquitous and sulfation is the most abundant known modification of tyrosine side chains. Choline sulfate and ascorbic acid 2-sulfate are also found in cells. Sulfate esters of phenols and many other organic sulfates are present in urine. 

A 23-year-old diabetic woman had severe subcutaneous insulin resistance for 11 years (169). Continuous subcutaneous insulin infusion with regular or insulin lispro did not prevent periods of fluctuating responses to insulin. The addition of heparin to insulin lispro in the pump improved serum insulin concentrations and metabolic control. The addition of heparin to regular insulin gave no improvement. 

An, D., Pulinilkunnil, T., Qi, D., Ghosh, S., Abrahani, A., and Rodrigues, B. 2005. The metabolic switch AMPK regulates cardiac heparin-releasable lipoprotein lipase. Am J Physiol Endocrinol Metab 288(1) E246-E253. 

M18. Mahley, R. W., and Weisgraber, K. H., Subfractionation of high density lipoproteins into two metabolically distinct subclasses by heparin affinity chromatography and Geon-Pevikon electrophoresis. In Report of the High Density Lipoprotein Methodology Workshop (K. Lippel, ed.), pp. 356-366. U.S. Department of Health, Education and Welfare. NIH publication No. 79-1661, Bethesda, Md., 1979. 

Heparin, H, is assumed to be metabolized by enzyme E to product M, which competes with the drug for binding sites on E. In addition, M, is biotransformed to M, which is non-competitive. If the mechanism given by equations f-3 is assumed and balances on H and M, are made for the reactor shown in Figure 1, the following model for heparin results (6)... 

Obtain 3 liters of fresh pig blood (see Supplies and Reagents section for an alternative supply of blood, if necessary) and immediately mix with heparin sulfate (30 mg/liter final concentration) to prevent clotting. Place the blood in an ice bucket and proceed. All additional steps through step 6 should be performed at 4°C. We suggest that steps 1 to 6 be performed by the instructor prior to the beginning of the experiment. If you plan to perform Experiment 16 (Experiments in Clinical Biochemistry and Metabolism ) in conjunction with this experiment, a... 

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