The behavior of pentaerythritol tetranicotinate in rat gastrointestinal tract as a prodrug.

ABSTRACT

The gas chromatographic assay method for pentaerythritol tetranicotinate, a nicotinic acid prodrug, and its hydrolysates was developed. The behavior of the drug in gastrointestinal tract was investigated in rat by using the method. The disappearance and hydrolysis of the drug were not observed in the gastric loop until 30 min. The rate of disappearance from the intestinal loop was 36.7% at 30 min which was significantly smaller than that of nicotinic acid. Little hydrolysis of the drug was observed in the buffer solution, pH 7.4, at 37 degrees up to 2 hr. However, the consecutive hydrolysis was observed when the drug was incubated with everted intestine or plasma. As to the rate of hydrolysis of the drug and its esterform hydrolysates by scraped intestinal mucosa, the ester to which the larger number of nicotinic acid was bound was hydrolyzed more rapidly. These results indicate that the orally administered drug is enzymatically hydrolyzed in the intestinal mucosa by a consecutive reaction. Although the hydrolysis rate of pentaerythritol tetranicotinate is rapid, the rate of its ester-form hydrolysate becomes slower gradually as the nicotinic acid is released. The released nicotinic acid is rapidly absorbed. The behavior of the drug revealed in this study suggests that pentaerythritol tetranicotinate is useful as a prodrug of nicotinic acid.