The in vitro pharmacological profile of SK&amp;F 106760, a novel GPIIB/IIIA antagonist

Vasko, J.; Valocik, Richard E.; Kopaciewicz, L J; Storer, Barbara; Ali, Fadia E.; Romoff, Todd T.; Calvo, Raul R.

doi:10.1016/0049-3848(94)90063-9

Cited by 13 publications

(9 citation statements)

References 20 publications

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“…At higher doses, increases in the duration of inhibition were observed. When SK&F 106760 was administered at 3 m g kg-l by bolus intraduodenal administration, a slow onset of inhibition of ex-vivo platelet aggregation was observed, which reached a maximal inhibition of ca 40% at approximately 60-195min after administration (Nichols et al 1994b). The same results were observed for SK&F 107260 (unpublished).…”

Section: Introduction: Peptide Drugs Vs Nonpeptide Drugssupporting

confidence: 61%

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Samanen

Wilson

Smith

et al. 1996

Journal of Pharmacy and Pharmacology

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This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided. The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260.

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Section: Introduction: Peptide Drugs Vs Nonpeptide Drugssupporting

confidence: 61%

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Samanen

Wilson

Smith

et al. 1996

Journal of Pharmacy and Pharmacology

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“…again very similar to what is known for mannitol (the oral absorption of mannitol is only about 17%). For other drugs, absorption by only the paracellular route has limited their effectiveness when administered orally (Gan et al 1993;Nichols et al 1994;Samanen et al 1996;Smith & Lee 2001).…”

Section: Discussionmentioning

confidence: 99%

S-adenosyl-l-methionine: transcellular transport and uptake by Caco-2 cells and hepatocytes

McMillan

Walle

2005

Journal of Pharmacy and Pharmacology

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S-adenosyl-L-methionine (SAMe) is an endogenous molecule that is known to be protective against hepatotoxic injury. Although oral SAMe appears to be absorbed across the intestinal mucosa, its systemic bioavailability is low. The reason for this is unknown. Using the Caco-2 cell culture model for enterocyte absorption, we determined the mode by which SAMe is transported across this cell monolayer. We also determined the extent it is taken up by both Caco-2 cells and hepatocytes. In Caco-2 cells transport was observed in both apical to basolateral and basolateral to apical directions. The apparent permeability coefficients (Papp) appeared to be concentration independent and were similar in both directions (0.7x10(-6) and 0.6x10(-6) cm s-1, respectively), i.e. identical to that of the paracellular transport marker mannitol (0.9x10(-6) and 0.7x10(-6) cm s-1). This mode of transport was supported by a four-fold increase in the Papp for SAMe transport in Ca++-free buffer. Cellular uptake of SAMe was examined in both Caco-2 cells and cultured rat hepatocytes. Uptake by hepatocytes was not saturable in a concentration range of 0.001-100 microM. Accumulation by both cell types was very low, with a cell:medium ratio at equilibrium of only 0.2-0.5. This low cell accumulation supports the finding of paracellular transport as the only mode of cell membrane transport. Increased hepatocellular protection for SAMe may be accomplished by converting SAMe to a more lipid-soluble prodrug.

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“…These findings are consistent with those obtained with other GPIIb/IIIa antagonists. 18,19) Platelet adhesion assay revealed that both agents inhibited platelet adhesion to vWF, fibrinogen, fibronectin and subendothelial matrix with similar potency. Both agents inhibited platelet adhesion to fibrinogen, fibronectin and subendothelial matrix up to the background level (BSA), suggesting that most of these adhesion phenomena involves platelet GPIIb/IIIa.…”

Section: Discussionmentioning

confidence: 99%

Comparative Studies of a Humanized Anti-glycoprotein IIb/IIIa Monoclonal Antibody, YM337, and Abciximab on in Vitro Antiplatelet Effect and Binding Properties.

Suzuki¹,

Sato²,

Kamohara³

et al. 2002

Biological & Pharmaceutical Bulletin

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The effects of YM337, the Fab fragment of a humanized anti-glycoprotein IIb/IIIa (GPIIb/IIIa) monoclonal antibody C4G1, on in vitro platelet function and binding properties were compared with those of abciximab, the Fab fragment of the human/murine chimeric anti-GPIIb/IIIa monoclonal antibody 7E3. Both agents completely inhibited platelet aggregation caused by all agonists tested except ristocetin. Further, both inhibited human platelet adhesion to von Willebrand factor, fibrinogen, fibronectin and subendothelial matrix with similar potency. Fibrinogen binding to washed platelets was dose-dependently inhibited by both agents. In binding assay using 125 I-YM337 and 125

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The in vitro pharmacological profile of SK&F 106760, a novel GPIIB/IIIA antagonist

Cited by 13 publications

References 20 publications

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

S-adenosyl-l-methionine: transcellular transport and uptake by Caco-2 cells and hepatocytes

Comparative Studies of a Humanized Anti-glycoprotein IIb/IIIa Monoclonal Antibody, YM337, and Abciximab on in Vitro Antiplatelet Effect and Binding Properties.

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