Comparative evaluation of absorption, distribution, and excretion of YM758, a novel If channel inhibitor, between albino and non-albino rats.
1. YM758 is a novel If channel inhibitor for the treatment of stable angina and atrial fibrillation. The absorption, distribution, and excretion of YM758 have been investigated in albino and non-albino rats after a single oral administration of (14)C-YM758 monophosphate. 2. YM758 was well absorbed from all segments of the gastrointestinal tract except for the stomach. After oral administration, the ratio of AUC(0-1 h) between the plasma concentrations of radioactivity and the unchanged drug was estimated to be 17.7%, which suggests metabolism. 3. The distribution of the radioactivity derived from (14)C-YM758 in tissues was evaluated both in albino and non-albino rats. The radioactivity concentrations in most tissues were higher than those in plasma, which indicates that the radioactivity is well distributed to tissues. Extensive accumulation and slower elimination of radioactivity were noted in the thoracic aorta of albino and non-albino rats as well as in the eyeballs of non-albino rats. The recovery rates of radioactivity in urine and bile after oral dosing to bile duct-cannulated albino rats were 17.8% and 57.3%, respectively. 4. These results suggest that YM758 was extensively absorbed, subjected to metabolism, and excreted mainly into the bile after oral administration to rats, and extensive accumulation of the unchanged drug and/or metabolites into tissues such as the thoracic aorta and eyeballs was observed.
Umehara
K-I
KI
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan. kenichi.umehara@jp.astellas.com
Seya
K
K
Sonoda
T
T
Nakamura
E
E
Noguchi
K
K
Usui
T
T
Kamimura
H
H
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001549:Benzamides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004764:Enterohepatic Circulation; D006339:Heart Rate / Q000187:drug effects; D007408:Intestinal Absorption; D007546:Isoquinolines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D020318:Rats, Long-Evans; D012849:Sinoatrial Node / Q000187:drug effects; D013045:Species Specificity; D014018:Tissue Distribution
D000889:Anti-Arrhythmia Agents; D001549:Benzamides; D007546:Isoquinolines; C530155:YM 758