RT Journal Article
SR Electronic
T1 Occupancy of the Internal and External Pools of Glycoprotein IIb/IIIa following Abciximab Bolus and Infusion
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 496
OP 500
VO 297
IS 2
A1 Martin J. Quinn
A1 Ross T. Murphy
A1 Michelle Dooley
A1 J. Brendan Foley
A1 Desmond J. Fitzgerald
YR 2001
UL http://jpet.aspetjournals.org/content/297/2/496.abstract
AB The internal pool of GPIIb/IIIa, which is expressed upon platelet activation, may be inaccessible to inhibition by GPIIb/IIIa antagonists. To determine the occupancy of the internal and external pools of GPIIb/IIIa and platelet function following an abciximab bolus and infusion, 15 patients undergoing elective percutaneous transluminal coronary angioplasty were administered abciximab as a bolus and 36-h infusion. GPIIb/IIIa receptor number and occupancy in resting and TRAP-6 (20 μM)-activated samples (to expose the internal pool of GPIIb/IIIa) was quantified using a monoclonal antibody-based assay. Antibody binding was quantified by flow cytometry and platelet inhibition by light transmittance aggregation and by the rapid platelet function analyser (Accumetrics, San Diego, CA). The target of >80% receptor occupancy (range 82–99% occupancy) of the external pool of GPIIb/IIIa was achieved in all patients at 3 min. Receptor occupancy of the combined internal and external pools of GPIIb/IIIa was less, ranging from 75 to 93% and again was maximal at 3 min. Platelet aggregation was markedly inhibited to 20 μM ADP (maximal, 11 ± 2% of baseline), but less so to 5 μM TRAP-6 (maximal, 36 ± 25% of baseline). Following discontinuation of the drug, there was a gradual fall in receptor occupancy over 15 days coinciding with the disappearance of abciximab from the platelet surface. Maximum inhibition of platelet function and receptor occupancy of the external pool of GPIIb/IIIa occurs within 3 min of an abciximab bolus and infusion. However, some internal receptors that are expressed by potent agonists are not occupied, which may explain the incomplete inhibition of platelet aggregation. The American Society for Pharmacology and Experimental Therapeutics