Background:

YM758 is a "funny" If current channel (If channel) inhibitor.

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].

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 t1/2 values of 1.62, 4.93, and 1.63 h, respectively. At the corresponding doses, the CLtot values amount to 1.71, 1.69, and 1.48 L/h/kg, and Vdss 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 t1/2 and Vdss 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 CLtot of YM758 in the blood basis (CLb,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].

[1]. Umehara K, et al. Hepatic uptake and excretion of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a novel if channel inhibitor, in rats and humans. Drug Metab Dispos. 2008 Jun;36(6):1030-8. [2]. Umehara K, et al. Relationship between exposure of (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide (YM758), a "funny" if current channel inhibitor, and heart rate reduction in tachycardia-induced beagle dogs. Drug Metab Dispos. 2009 Jul;37(7):1427-33. [3]. Umehara K, et al. Investigation of long-term retention of unchanged (-)-N-{2-[(R)-3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidino]ethyl}-4-fluorobenzamide, a novel "funny" If current channel inhibitor, and its metabolites in the eyeball and thoracic aorta of rats. Drug Metab Dispos. 2009 Nov;37(11):2137-44.