Linked Life Data

9172954

Source:http://linkedlifedata.com/resource/pubmed/id/9172954

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1997-6-5
pubmed:abstractText
L-738,167 is a potent and long-acting fibrinogen receptor antagonist and may be useful for treatment of chronic thrombotic occlusive disorders. The purposes of this study were to characterize the metabolism and disposition of L-738,167, and to investigate factors affecting its pharmacokinetic behaviors in dogs, one of the animal models used in pharmacological and toxicological studies. In vitro and in vivo experiments indicated that L-738,167 was not metabolized to any appreciable extent in dogs. Biliary excretion was found to be the major route (approximately 75%) of drug elimination. Following 1 and 3 micrograms/kg iv doses, blood pharmacokinetics of L-738,167 were linear. Total blood clearance (CLB) was much lower than hepatic blood flow, and the apparent volume of distribution at steady-state (Vdss,B) was comparable with blood volume. Blood pharmacokinetics in the dose range of 3-250 micrograms/kg were dose-dependent; both CLB and Vdss,B for L-738,167 increased markedly with increasing doses. However, the terminal half-life (t1/2) was dose-independent, with a mean value of approximately 4 days. L-738,167 was found to bind negligibly to dog plasma proteins. Determinations of whole blood (WB), platelet-rich plasma, and platelet-poor plasma concentrations after several intravenous doses of [3H]L-738,167 revealed significant concentration-dependent binding of the compound to platelets. Kinetic analysis of the platelet binding indicated that L-738,167 was bound to dog platelets with high affinity (apparent Kd approximately 1 nM platelet-poor plasma concentration) and relatively low capacity (approximately 70 nM WB concentration). Findings are consistent with the binding kinetics of L-738,167 to glycoprotein IIb/IIIa (GP IIb/IIIa) receptor, supporting that GP IIb/IIIa was the primary binding component on the platelets. It was concluded that the dose-dependent pharmacokinetics of L-738,167 were the consequence of the concentration-dependent drug-platelet binding. Due to this extensive platelet binding, L-738,167, when given in therapeutic doses or lower, resided primarily in the vascular compartment-the site of pharmacological action. At doses exceeding the receptor binding capacity, the excess amount or the unbound drug was eliminated rapidly. In all cases, the equally long t1/2 of L-738,167 was also a consequence of the high-affinity binding to platelets, in good agreement with its prolonged pharmacodynamic profile.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0090-9556
pubmed:author
pubmed:issnType
Print
pubmed:volume
25
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
355-61
pubmed:dateRevised
2003-11-14
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
Disposition of L-738,167, a potent and long-acting fibrinogen receptor antagonist, in dogs. Dose-dependent pharmacokinetics.
pubmed:affiliation
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
pubmed:publicationType
Journal Article