Thrombin pharmacokinetics

One molecule of lepirudin binds to one molecule of thrombin and thereby blocks the thrombogenic activity of thrombin. As a result, all thrombin-dependent coagulation assays are affected (eg, aPTT values increase in a dose-dependent fashion). Pharmacokinetics ... 

Mechanism of Action A direct thrombin inhibitor that reversibly binds to thrombin-active sites. Inhibits thrombin-catalyzed or thrombin-induced reactions, including fibrin formation, activation of coagulant factors V, VIII, and XIII also inhibits protein C formation, and platelet aggregation. Therapeutic Effect Produces anticoagulation. Pharmacokinetics Following IV administration, distributed primarily in extracellular fluid. Protein binding 54%. Metabolized in the liver. Primarily excreted in the feces, presumably through biliary secretion. Half-life 39-51 min. 

Gustafsson D, Elg M. The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran a mini-review. Thromb Res 2003 109(suppl I ) S9-S I 5. 

Eriksson UG, Bredberg U, Gislen K, et al, Pharmacokinetics and pharmacodynamics of ximelagatran, a novel oral direct thrombin inhibitor, in young healthy male subjects. Eur J Clin Pharmacol 2003 59 35-43. 

Wahlander K, Eriksson-Lepkowska M, Frison L, etal. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor. Clin Pharmacokinet 2003 42 755-764. 

Sarich TC, Schutzer KM, Dorani H, et al. No pharmacokinetic or pharmacodynamic interaction between atorvastatin and the oral direct thrombin inhibitor ximelagatran. J Clin Pharmacol 2004 44 928-934. 

Bredberg E, Andersson TB, Frison L, et al. Ximelagatran, an oral direct thrombin inhibitor, has a low potential for cytochrome P450-mediated drug-drug interactions. Clin Pharmacokinet 2003 42 765-777. 

Sarich TC, Teng R, Peters GR, et al. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. Clin Pharmacokinet 2003 42 485 -92,... 

StangierJ, Eriksson Bl, Dahl OE, etal. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005 45 555-563. 

The thrombin inhibitor argatroban had no effect on the steady-state pharmacokinetics of oral digoxin 0.375 mg/day in 12 healthy volunteers the argatroban was given as an intravenous infusion of 2 micrograms/kg/minute on days 11-15 (236). 

Hauptmaim J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. A review of small-molecule thrombin inhibitors. Eur J Chn Pharmacol 2002 57(ll) 751-8. 

Thrombin inhibitors like o-Phe-Pro-Arg aldehyde have been known for a long time. However, the compounds lacked oral bioavailability. A semi-rational approach was adopted to modify Pj to Pj positions to improve the potency, selectivity and pharmacokinetic properties. Changes in individual positions were followed by multiple changes and synthesis of conformationally restricted analogues, Substitution of the C-terminal arginine aldehyde moiety (Pj position) by p-amidinobenzylamine gave... 

In addition to its intrinsic reduced affinity for thrombin, the higher doses required for inhibitor 7 may be correlated to its pharmacokinetics and metabolic susceptibility. The t /2p of r-hirudin and inhibitor 7 were approximately the same in the rat (25-30 minutes) while for the low molecular weight inhibitor 7 it is less than 3 minutes. It is well known that the kidney serves as the primary site of elimination of many polypeptide based drugs [77]. Indeed hirudin is excreted intact in the urine of several species [78]. We found that differences in the rate of elimination between inhibitors 4 and 7 may be explained in part by differences in the metabolic susceptibility toward rat kidney membrane proteases. The principal result from these studies is that the truncated inhibitor 7 is much more proteolytically labile compared to 4 in vitro. In 7, the proteolytic products arise rmidly (< 5 min) firom the cleavage of the Phe -Glu bond followed by cleavage of Asp -Phe, both of which are sufficient to inactivate the peptide. In inhibitor 4, three principal proteolytic sites were identified, two of which are within the spacer residues 1) Leu -Gln 2) Asn -Asp and 3) Gln -Ser . However, intact compound could still be detected after 30 minutes. 

Lave, T. et al.. Interspecies pharmacokinetic comparisons and allometric scaling of napsagartran, a low molecnlar weight thrombin inhibitor, J. Pharm. Pharmacol., 51 85-91, 1999. 

Teng R, Sarich TC, Eriksson UG, Hamer JE, Gillette S, Schutzer KM, Carlson GF, Knowey PR. A pharmacokinetic study of the combined administration of amiodarone and ximelagatran, an oral direct thrombin inhibitor. J Clin Pharmacol (2004) 44, 1063-71. 

Dorani H, Schutzer K, SarichTC, Wall U,OhlssonL, Eriksson UG. Effect of erythromycin on the pharmacokinetics and pharmacotfynamics cr the oral direct thrombin inhibitor ximelagatran and its active form melagatran Clin Pharmacol Ther (2004) 75, P78... 

Greish, K. et al., 2003. Macromolecular therapeutics advantages and prospects with special emphasis on tumour targeting. Clinical Pharmacokinetics, 42(13), 1089-1105. Griffin, L.C. et al, 1993. In vivo anticoagulant properties of a novel nucleotide-based thrombin inhibitor and demonstration of regional anticoagulation in extracorporeal... 

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