Superiority of plasma 11-dehydro-TXB2 to TXB2 as an index of in vivo TX formation in rabbits after dosing of CS-518, A TX synthase inhibitor

We compared plasma 11-dhTXB2 and TXB2 for their ability to reflect in vivo TX formation in rabbits treated with AA and CS-518, a TX synthase inhibitor. The average plasma level of TXB2 in rabbits was much higher than that of 11-dhTXB2, probably because of artificial formation of TXB2 during blood sampling. CS-518 (1 mg/kg, p.o.) caused a long-lasting suppression of the 11-dhTXB2 level, and its inhibitory effect on 11-dhTXB2 was much more extensive than that on TXB2. AA-infusion for 5 min resulted in transient and remarkable increases of both TXs, and prevention of such increases by CS-518 pretreatment (1 mg/kg, i.v.) was shown: inhibitions of 11-dhTXB2 and TXB2 were 85% and 40%, respectively. The inhibitory effect caused by CS-518, which was more clearly observed on plasma 11-dhTXB2 than on TXB2, was due to not only the completely inhibited levels without artificial formation but also the durable high levels based on the long half-life of 11-dhTXB2 in AA-infused rabbits. CS-518 injection during sustained AA-infusion also resulted in a 2-fold faster disappearance of plasma 11-dhTXB2 than was seen without CS-518, despite its long half-life. Considering the absence of artificial formation, the long half-life, and the good response to change of TX formation, plasma 11-dhTXB2 is superior to TXB2 as an index for monitoring in vivo TX synthase activity and its pharmacological modification with AA and CS-518.