Sequential group trial to determine gastrointestinal site of absorption and systemic exposure of azathioprine

Azathioprine (AZA) is used in the treatment of patients with refractory inf lammatory bowel disease; however, its use is limited because of systemic to xicity associated with long-term use. Ileocecal delivery of AZA might be ad vantageous if local intestinal therapeutic effects could be provided with d ecreased systemic side effects. Decreased cecal systemic absorption would a llow higher dosages of AZA to be administered. A two-phase study was perfor med to compare the systemic exposure of AZA and 6-mercaptopurine (6-MP) fol lowing administration of AZA into the stomach, jejunum, and cecum and to co mpare the systemic exposure to AZA and 6-MP following administration of thr ee different dosages of AZA into the cecum. In phase I, six healthy male vo lunteers received three 50 mg sequential doses of AZA via an oral tube dire ctly placed into the stomach, jejunum, and cecum, respectively. In phase II , six healthy male volunteers received three different dosages (50, 300, 60 0 mg of AZA) into the cecum. Plasma concentrations of AZA and 6-MP at vario us times were quantified and area under the plasma concentration-time curve (AUC) and mean residence time (MRT) were determined. No significant differ ences in the AUC of AZA were seen at the different sites. The AUC of 6-MP f ollowing administration of AZA into the jejunum (67.0 +/- 30.1 ngxhr/ml) wa s higher compared to the stomach (39.9 +/- 38.1 ng/hr/ml) and cecum (29.2 /- 10.9 ngxhr/ml). Jejunal absorption was 68% higher than absorption from t he stomach and 129% higher than that of the cecum. Gastric absorption was 2 7% higher than that of the cecum. Increased dosages given into the cecum re sulted in increased AUCs of AZA and 6-MP. The AUCs of AZA following 50, 300 , and 600 mg dosages were 16.9 +/- 7.4, 52.3 +/- 67.2, and 132 +/- 151 ngxh r/ml, respectively, and the AUCs of 6-MP were 22.2 +/- 14.9, 63.4 +/- 50.6, and 104 +/- 115 ngxhr/ml, respectively. Systemic exposure to 6-MP is reduc ed following administration of AZA into the cecum, most likely secondary to reduced absorption of 6-MP from the colon. Higher dosages of AZA presented to the cecum do result in increased systemic absorption, but may still all ow more drug to be administered with less toxicity than the same dose recei ved orally.