METABOLIC POLYMORPHISM OF E6123 IN RHESUS-MONKEY

1. The metabolic polymorphism of a new thienodiazepine platelet activa ting factor receptor antagonist (E6123) in rhesus monkey was studied i n vivo and in vitro. 2. After i.v. dosing of C-14-E6123, the levels of radioactivity in blood, plasma and red blood cells were higher in poo r metabolizers (PMs) with AUC(0-24h) values which were about 1.3-1.5 t imes higher than those in extensive metabolizers (EMs). 3. After i.v. dosing of C-14-E6123, radioactivity was excreted rapidly by both EMs a nd PMs. However, EMs excreted the radioactivity mainly in urine wherea s, for PMs, radioactivity was excreted fairly equally in urine and fae ces. 4. In vivo and in vitro studies demonstrated that the metabolic p olymorphism of E6123 in rhesus monkey is caused by a difference in the hydrolysis of an amide side chain. 5. Our results suggested that ther e are two types of the enzymes which metabolize E6123 by this route in EMs, but only one type in PMs. 6. The low affinity enzyme in EMs migh t be the same as the enzyme in PMs, indicating that the metabolic poly morphism of E6123 in rhesus monkey could depend on the existence of a high affinity enzyme.