Absorption, distribution, metabolism and excretion of YM466, a novel factor Xa inhibitor, in rats

Abstract

YM466 is a novel factor Xa inhibitor for the treatment of thrombosis. The absorption, distribution, metabolism and excretion of YM466 were investigated in male Fisher rats after a single oral administration. YM466 was absorbed rapidly from all segments of the gastrointestinal tract except the stomach. After oral dosing, the plasma concentration of (14)C-YM466 reached a maximum within 0.5 h, and declined rapidly with an elimination half-life of 0.64 h. The unchanged YM466 accounted for almost all of its radioactivity, suggesting a minimal metabolism in rats. This was also supported by the finding that no metabolites were observed in bile and urine after oral dosing of (14)C-YM466. The distribution of (14)C-YM466 in tissue was evaluated and the liver and kidney were the organs with radioactivity concentrations consistently higher than that of plasma. Cumulative biliary and urinary excretion of radioactivity in bile duct-cannulated rats was 29.5% and 7.6%, respectively, indicating prominent excretion into bile after oral dosing. This was consistent with the finding that 76.1% and 25.2% of radioactivity dosed were excreted to faeces and urine, respectively, after i.v. dosing. These results suggest that YM466 was rapidly absorbed and then subjected to biliary excretion with a minimal metabolism after oral dosing to rats.

Hepatobiliary transport of YM466, a novel factor Xa inhibitor, in rats

“…A previous pharrnacokinetic study in rats revealed that YM466 was only minimally metabolized, followed by its excretion into the bile and urine in unchanged form [5]. In the tissue distribution study, the tissue-to-plasma concentration ratio of Y M466 in the liver was the highest among the 23 tissues investigated [5]. These observations suggest that, in rats, YM466 is efficiently taken up into the liver and excreted into the bile.…”

“…Previous studies in rats have demonstrated that YM466 is minimally metabolized [5] and is excreted into the bile and urine in unchanged form [5]. Thus, hepatobiliary excretion is one of the important elimination pathways for YM466.…”

“…1) is a novel factor Xa inhibitor which has been found to possess potent anti-thrombotic activity in several animal models, including rats [1,2], guinea pigs [3],and squirrel monkeys [4]. A previous pharrnacokinetic study in rats revealed that YM466 was only minimally metabolized, followed by its excretion into the bile and urine in unchanged form [5]. In the tissue distribution study, the tissue-to-plasma concentration ratio of Y M466 in the liver was the highest among the 23 tissues investigated [5].…”

A liquid chromatographic–tandem mass spectrometric method for the determination of YM466, a novel Factor Xa inhibitor, in rat plasma

“…After oral dosages of YM466 to rats, YM466 was not subjected to metabolism [2], and exhibited anticoagulant activity [3,4]. In order to estimate the effective plasma concentration of YM466 in rats, a sensitive analytical method is necessary.…”

Aminoalkylmethacrylate copolymer E improves oral bioavailability of YM466 by suppressing drug–bile interaction

“…For every day clinical use, oral medication has been desired for factor Xa inhibitors 1. Therefore, oral bioavailability of YM466 was investigated in rats and dogs, but the values were very low (rats, 4%; dogs, 7%)3 and the reason for it has been thought to be its poor oral absorption 3,4. Recently, we have examined the factors affecting the gastrointestinal absorption of YM466 and found that the membrane permeability of YM466 itself is high enough to be around 30%–40% fraction of dose absorbed in human, whereas YM466 interacts with bile to form a poorly soluble complex, which would lead to the poor absorption of YM466 after oral administration 5.…”