On the mechanism of the prolonged action in man of GR32191, a thromboxane receptor antagonist.
Twenty four healthy men were treated with GR32191, a thromboxane receptor antagonist with a long duration of action, in a double blind placebo-controlled crossover study. Platelet aggregation in response to a thromboxane (TX) mimetic (U46619) was studied turbidometrically using platelet rich plasma (PRP) prepared 12 h after dosing (80 mg po) and 1.5 h after a second dose (40 mg po). To determine whether the long lasting inhibition caused by GR32191 is associated with persistent inhibitory activity in plasma (from residual drug or from an active metabolite), platelet poor plasma (PPP) from treated subjects was mixed with PRP from placebo treated controls. 12 h after dosing this caused 40-80% inhibition, consistent with the plasma concentration of GR32191. Inhibition of U46619 in PRP from GR32191 treated subjects mixed with PPP from controls was even greater (essentially 100%). We conclude that the prolonged activity of GR32191 is due in part to a reduction in available thromboxane receptors and in part to its persistence in plasma for longer than had previously been appreciated.
Ritter
J M
JM
Department of Clinical Pharmacology, UMDS, Guy's Hospital, London.
Doktor
H S
HS
Benjamin
N
N
Barrow
S E
SE
Stewart-Long
P
P
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000293:Adolescent; D000328:Adult; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D004311:Double-Blind Method; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011897:Random Allocation; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000502:physiology; D013929:Thromboxane B2 / Q000096:biosynthesis
D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013929:Thromboxane B2; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C060013:vapiprost