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Abstract
1. The metabolic polymorphism of a new thienodiazepine platelet activating factor receptor antagonist (E6123) in rhesus monkey was studied in vivo and in vitro.
2. After i.v. dosing of 14C-E6123, the levels of radioactivity in blood, plasma and red blood cells were higher in poor metabolizers (PMs) with AUC(0-24h) values which were about 1.3–1.5 times higher than those in extensive metabolizers (EMs).
3. After i.v. dosing of 14C-E6123, radioactivity was excreted rapidly by both EMs and PMs. However, EMs excreted the radioactivity mainly in urine whereas, for PMs, radioactivity was excreted fairly equally in urine and faeces.
4. In vivo and in vitro studies demonstrated that the metabolic polymorphism of E6123 in rhesus monkey is caused by a difference in the hydrolysis of an amide side chain.
5. Our results suggested that there 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 might be the same as the enzyme in PMs, indicating that the metabolic polymorphism of E6123 in rhesus monkey could depend on the existence of a high affinity enzyme.