Effect of altering small bowel transit time on sustained release theophylline absorption

The relationship between variations in small bowel transit time (SBTT) and the absorption of theophylline from a sustained-release product was evaluated in a three-way, randomized, crossover study in 12 healthy male nonsmokers. Subjects received sustained-release theophylline (600 mg) with loperamide (8 mg every 6 hour x 8 doses). metoclopramide (15 mg every 6 hour x 8 doses) or placebo (every 6 hour x 8 doses). Theophylline solution (400 mg) was used as a reference standard. Serum samples were collected periodically for 72 hours for theophylline concentration determinations. SBTT was measured by the lactulose hydrogen breath test. Compared with placebo (98 +/- 53 min), SBTT was increased with loperamide (211 +/- 87 min; P less than 0.001) and decreased with metoclopramide (55 +/- 18 min; P less than 0.001). Loperamide decreased the rate, but not the extent of theophylline absorption from this product. This was evident from the reduced Cmax, the prolonged Tmax, and the decreased fraction of the dose absorbed at 24 hours, while the area under the curves remained the same. In contrast, metoclopramide had no effect either on rate or extent of absorption. The data suggest that the effect of loperamide on these absorption parameters was due to an increase in the dissolution time of this sustained-release product.