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 microg 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 microg 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 (AUCt) and maximum plasma concentration (Cmax) 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 (t1/2). However, significant (P < 0.05) changes in the time to reach Cmax (tmax) 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 pre-treatment with erythromycin (0.9 h and 0.5-1.3).


CONCLUSIONS
Presumably due to slower gastrointestinal motility, pretreatment with loperamide significantly increases the gastrointestinal absorption of desmopressin. Except for a shortening of tmax pretreatment with erythromycin did not significantly influence absorption of the drug.
Callréus
T
T
Department of Clinical Pharmacology, Lund University Hospital, Sweden.
Lundahl
J
J
Höglund
P
P
Bengtsson
P
P
D000328:Adult; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D003894:Deamino Arginine Vasopressin / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004917:Erythromycin / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000494:pharmacology*; D005769:Gastrointestinal Motility / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D008139:Loperamide / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D012076:Renal Agents / Q000009:adverse effects / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D005765:Gastrointestinal Agents; D012076:Renal Agents; D004917:Erythromycin; D008139:Loperamide; D003894:Deamino Arginine Vasopressin