Changes in gastrointestinal motility influence the absorption of desmopressin

Objective: The antidiuretic effect of desmopressin is widely utilized in the treatment of neurogenic diabetes insipidus and nocturnal enuresis in children. The objective of the present study was to assess how changes in gastrointestinal motility, induced by erythromycin and loperamide, influence the pharmacokinetics of orally administered desmopressin. Methods: This study was conducted using an open randomized, three-period, three-treatment design in 18 healthy subjects. On each study day a single oral dose of 400 mu g desmopressin was administered in the morning. The desmopressin dose was either given alone (reference) or after pretreatment with either loperamide tablets (4 mg at -24, -12 h and -1 h) or erythromycin capsules (250 mg q.i.d, with the first dose in the morning 3 days before the study day and the last dose at -1 h). On each study day, blood was sampled up to 8 h after dosing for assessment of desmopressin concentration. Results: Compared with administration of 400 mu g of desmopressin alone, pretreatment with loperamide produced significantly(P < 0.05) altered pharmacokinetics of desmopressin as the endpoints; area under the curve up to infinity (AUC), area up to the last determinable plasma concentration (AUC,) and maximum plasma concentration (C-max) increased 3.1-fold (95% CI 2.3-4.2), 3.2 (2.3-4.4) and 2.3 (1.6-3.2), respectively. Although the estimates were lower, pretreatment with erythromycin did not result in any significant changes in these endpoints. There were no significant changes observed between the three treatments regarding the terminal elimination half-life (t(1/2)) However, significant (P < 0.05) changes in the time to reach C-max (t(max)) values (median and range) were observed as, compared with administration of desmopressin alone (1.3 h and 0.5-4.0), it was longer after pretreatment with loperamide (2.0 h and 0.5-3.0) and shorter following pretreatment with erythromycin (0.9 h and 0.5-1.3). Conclusion: Presumably due to slower gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal absorption of desmopressin. Except for a shortening of t(max), pretreatment with erythromycin did not significantly influence absorption of the drug.