Menthol-β-D-Glucuronide: A Potential Prodrug for Treatment of the Irritable Bowel Syndrome

Abstract

Menthol-β-D-glucuronide is a potential prodrug for colonic delivery of the spasmolytic agent menthol. Menthol is the primary constituent of peppermint oil, which is used to treat the irritable bowel syndrome. The chemical stability of menthol-β-D-glucuromde was assessed at various pHs (1.5,4.5, 6.0 and 7.4) over a 4 to 24 h period at 37°C. The prodrug was stable, i.e., there was less than 0.1% hydrolysis of the prodrug, at pHs of 4.5, 6.0 and 7.4. At pH 1.5, the prodrug was about 20% hydrolyzed over a 4 h period suggesting the need for an enteric coating to prevent premature hydrolysis in the stomach. The stability of the prodrug was also assessed in luminal contents of the laboratory rat and in human stool samples. These studies were performed at concentrations designed to assess relative velocities of hydrolysis (i.e., substrate concentrations in excess of the K_m). The prodrug was stable in luminal contents of the rat stomach, proximal small intestine, and the distal small intestine. The rate of hydrolysis of menthol-β-D-glucuronide was 6.26 ± 2.88 nmol min^−l mg^−l and 2.34 ± 1.22 nmol min^−l mg^−l in luminal contents of the rat cecum and colon, respectively. The hydrolysis rate of menthol-β-D-glucuronide was lower in human stool samples (0.52 ± 0.46 nmol min⁻¹ mg^−!). The prodrug had a measured log octanol/buffer partition coefficient of −1.61 suggesting it should be poorly absorbed from the lumen of the gastrointestinal tract. The data support the hypothesis that menthol-β-D-glucuronide is a candidate for the delivery of menthol to the large intestine under in vivo conditions.