title: Pharmacokinetics of YK754, a novel If channel inhibitor in rats, dogs and humans.
abstract: The pharmacokinetics of YM758, a novel funny If current channel (If channel) inhibitor, was investigated after single intravenous (i.v.) and oral dosing to rats and dogs, and partially compared with the results in humans by using liver microsomes. After i.v. administration, the plasma YM758 concentrations decreased, with an elimination half-life (t(1/2)) of 1.14-1.16 h in rats and 1.10-1.30 h in dogs. Total body clearance (CL(tot)) was 5.71-7.27 and 1.75-1.90 L/h/kg in rats and dogs, respectively which was comparable to the hepatic blood flow rate. In dogs, the pharmacokinetic profiles for i.v. bolus administration and continuous infusion did not differ. After oral administration, the levels of YM758 in rat plasma increased more than dose-proportionally, whereas almost linear pharmacokinetics were observed in dogs. Absolute bioavailability was 7.5%-16.6% in rats and 16.1%-22.0% in dogs. The plasma protein binding saturation of YM758 was observed in dogs and humans; this finding is consistent with the result that the major binding protein of YM758 in plasma is alpha1-acid glycoprotein (AGP), in particular in humans. The blood-to-plasma partition coefficient values were 1.36-1.42 in rats, 0.95-1.15 in dogs and 0.71-0.85 in humans. The results of the metabolic study on liver microsomes indicated that the non-linear pharmacokinetics of YM758 observed in rats may be partially due to a first-pass effect in the gastrointestinal tract and the liver.
authors.affiliation: Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.
authors.forename: K-I
authors.initials: KI
authors.lastname: Umehara
authors.forename: T
authors.initials: T
authors.lastname: Nakamata
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Noguchi
authors.forename: T
authors.initials: T
authors.lastname: Usui
authors.forename: H
authors.initials: H
authors.lastname: Kamimura
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001773:Blood Cells / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels / Q000037:antagonists & inhibitors*; D004285:Dogs; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
chemical_list: D001798:Blood Proteins; D054815:Cyclic Nucleotide-Gated Cation Channels; C532247:N-(2-(3-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)piperidinio)ethyl)-4-fluorobenzamide; D044005:Tetrahydroisoquinolines
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