Zatebradine: Pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects

Identification of Human Metabolites 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, and Investigation of the Transporter-Mediated Renal and Hepatic Excretion of These Metabolites

“…Recent studies have called attention to the pharmacological properties of a novel class of specific bradycardic agents such as zatebradine and ivabradine. These compounds have been reported to reduce heart rate in clinical trials without any concomitant negative inotropic or hypotensive effects, and ivabradine has recently entered the market as an agent for stable angina (Indolfi et al, 1989;Roth et al, 1993). Heart rate reduction induced by these agents is reported to be due to the inhibition of the "funny" If current channel (If channel) expressed in the sinus node (Bucchi et al, 2007).…”

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

“…More recently, the pharmacological properties of a novel class of specific bradycardic agents, such as zatebradine and ivabradine, were clarified. These compounds reportedly reduced the heart rate (HR) in clinical trials without any concomitant negative inotropic or hypotensive effects; in fact, ivabradine recently entered the market as an agent for stable angina (Indolfi et al, 1989;Roth et al, 1993;Bucchi et al, 2007). It was also reported that the HR reduction induced by this kind of agent was the result of the inhibition of the "funny" If current channel (If channel) expressed in the sinus node (Bucchi et al, 2007).…”

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

“…1). The pharmacological properties of these compounds as specific bradycardic agents have been clarified, and they reportedly reduced heart rate in clinical trials without any concomitant negative inotropic or hypotensive effects; in fact, ivabradine recently entered the market as an agent for stable angina (Indolfi et al, 1989;Roth et al, 1993;Bucchi et al, 2007). It was also reported that the heart rate reduction induced by this kind of agent was due to the inhibition of the If channel expressed in the sinus node (Bucchi et al, 2007).…”

“…It was also reported that the heart rate reduction induced by this kind of agent was due to the inhibition of the If channel expressed in the sinus node (Bucchi et al, 2007). Although the pharmacokinetic and excretion profiles of zatebradine have already been investigated in a study of a single administration of [ 14 C]zatebradine to humans (Roth et al, 1993), information on the drug metabolism and pharmacokinetics of If channel inhibitors is still limited. Therefore, we investigated the disposition of YM758, one If channel inhibitor, from which several useful pieces of information were gained: 1) the pharmacokinetic profile is linear in rats and dogs, and the first-pass effect exists (Umehara et al, 2008a); 2) the major binding protein of YM758 in plasma was estimated to be ␣ 1 -acid glycoprotein (Umehara et al, 2008a); 3) the hepatic uptake and excretion of YM758 are mediated via organic anion transporter 1B1 and P-glycoprotein, respectively (Umehara et al, 2008b); 4) CYP3A4 and CYP2D6 mediate the oxidative metabolism of YM758 (Umehara et al, 2008c); 5) P-glycoprotein, not breast cancer resistance protein, Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.…”