AG-045572

AG-045572 is a GnRH receptor antagonist with K_is of 6.0 nM and 3.8 nM for human and rat GnRH receptor，respectively. AG-045572 is metabolized by CYP3A and ressuppresses testosterone^[1]. In Vitro:AG-045572 (10 μM，40 min，for human liver microsomes; 10 μM，10 min，for male rat liver microsomes; 1 μM，10 min，for female rat liver microsomes) is metabolized by CYP3A4 (HY-P74210) in both rats and humans with the K_m values were similar in male and female human，female rat liver microsomes，and expressed CYP3A4 and CYP3A5 (0.39，0.27，0.28，0.25，and 0.26 μM，respectively)，and the K_m in male rat liver microsomes was 1.5 μM，suggesting that in male and female rats AG-045572 is metabolized by different CYP3A isozymes^[1]. In Vivo:AG-045572 (10 mg/kg (i.v.) or 20 mg/kg (p.o.)，one time) give to intact male rats，it showed medium T_1/2，CL and V_ss but oral bioavailability was low，in female rats the bioavailability was much higher (24%)，in castrated male rats the pharmacokinetics was similar to that in female rats^[1].
AG-045572 (40 mg/kg，i.m. twice a day for 3 days) pretreated of intact male rats resulted in a change of its pharmacokinetics，the parameters became similar to those in female and castrated male rats^[1].
Pharmacokinetic Parameters of AG-045572 in Rats after Administration at 10 mg/kg i.v. and 20 mg/kg p.o.^[1]

Pharmacokinetic Analysis^[1]

Animals	t1/2 (h)	CL (L/h/kg)	Vss (L/kg)	Cmax (μM)	Tmax (h)	Fp.o. (%)
Male	1.4 ± 0.1	2.2 ± 0.5	2.1 ± 0.1	0.61 ± 0.21	1	8
Female	1.7 ± 0.1	1.5 ± 0.1	2.7 ± 0.4	2.31 ± 0.57	1	24
Castrated male	1.7 ± 0.4	1.5 ± 0.3	3.7 ± 1.5	1.98 ± 0.51	1	23
Pretreated male	1.9 ± 0.2	1.5 ± 0.2	2.0 ± 0.6	1.89 ± 0.41	1	27