YM758

YM758 is a “funny” I_f current channel (I_f channel) inhibitor. IC50 & Target:I_f channel^[1] In Vitro: The inhibitory effect of YM758 on [³H]MPP uptake via human/rat organic cation transporters (hOCT1/rOct1) is investigated. YM758 inhibits rOct1- and hOCT1-mediated [³H]MPP uptake in a concentration-dependent manner with IC₅₀ values of 23.8 and 40.5 μM, respectively. The IC₅₀ value of YM758 for [¹⁴C]Metformin uptake via rOct1 may be estimated below 10 μM in the same way, whereas that is much smaller than that for [³H]MPP uptake. In addition, the inhibitory effect of YM758 on [³H]E₂17βG uptake via OATP1B1 and OATP1B3 is investigated. YM758 inhibits OATP1B1-mediated [³H]E₂17βG uptake in a concentration-dependent manner with a IC₅₀ value of 13.0 μM. YM758 has no inhibitory effect on OATP1B3-mediated [³H]E₂17βG uptake^[1]. In Vivo: After a single intravenous administration of 0.03, 0.1, and 0.3 mg/kg to tachycardia-induced beagles, YM758 plasma concentrations rapidly decrease with t_1/2 values of 1.62, 4.93, and 1.63 h, respectively. At the corresponding doses, the CL_tot values amount to 1.71, 1.69, and 1.48 L/h/kg, and Vd_ss values are 3.19, 5.78, and 2.94 L/kg, respectively. Because the plasma concentration 24 h after administration is quantified only in the 0.1 mg/kg dosing group, the larger values of t_1/2 and Vd_ss are obtained compared with those in other dosing groups. The PK profile of YM758 in tachycardia-induced dogs appeares to be linear within the dose range of 0.03 to 0.3 mg/kg. The CL_tot of YM758 in the blood basis (CL_b,dog) is estimated to be 1.47 to 1.69 L/h/kg^[2]. The radioactivity in the rat eyeballs after dosing ¹⁴C-YM758 is extracted with a mixture of 2 mol/L hydrochloric acid and Methanol (5:95, v/v); the radioactivity recovery is 97.1% at 4 h and 67.1% at 24 h. The HPLC recovery of radioactivity from the extracted samples is 90.6 and 100.6% at 4 and 24 h, respectively. In the eyeball at 4 h after administration, YM758 (the unchanged drug) is the main compound detected (66.7%), and the metabolites YM-252124 (14.5%), YM-394111 (2.4%), and YM-234903 (1.8%) are also observed^[3].