INTRODUCTION:
Prucalopride is a selective, high-affinity agonist of the 5-hydroxytryptamine-4 (5-HT4) receptor and is indicated for the treatment of adult patients with chronic constipation. In humans, prucalopride is rapidly absorbed and extensively distributed, reaching maximum plasma concentration 2–3 h after a 2 mg oral dose. We report three studies investigating tissue distribution of prucalopride in rats.
METHODS:
A single oral dose of 14C-labelled prucalopride at 5mg base-equivalent(eq)/kg was administered to 30 SPF Wistar rats (5 males, seven groups of 3 non-pregnant females and 4 pregnant females [dose administered on day 18 of gestation]). Total radioactivity (TR) in various tissues was measured up to 96h. In females, the area under the TR concentration curve for up to 8h (AUC0–8h) and the AUC0–8h tissue:plasma ratio was calculated. The tissue concentration of unchanged drug (UD) was measured up to 48 h.
RESULTS:
The highest mean TR for all rats was detected in the pancreas (8.9µg-eq/g within 30 min of dosing; below the limit of detection [LOD] after 24 h), the liver (12.5 µg-eq/g within 20 min; 0.3 µg-eq/g after 96 h) and the small intestine (15.6µg-eq/g within 30 min; below the LOD after 24 h). The highest mean concentration of UD in non-pregnant females was detected in the small intestine (10.1 µg-eq/g within 20 min; below the LOD after 24 h). The lowest mean TR was detected in the brain, in males (0.12 µg-eq/g within 30 min), non-pregnant females (0.21 µg-eq/g within 1 h) and pregnant females (0.21 µg-eq/g within 30 min). TR in the brain was below the LOD within 2, 24 and 8 h of dosing, respectively. In non-pregnant females, the highest AUC0–8h and AUC0–8h tissue:plasma ratios of TR were observed in the small intestine (75.3 and 31.3, respectively); the lowest values were observed in the brain (0.85 and 0.35, respectively). Findings were similar for UD. In pregnant females the highest AUC0–8h and AUC0–8h tissue:plasma ratios of TR were observed in rectal (mucosa) and salivary gland tissue (122 and 20.5, respectively, for both); the lowest values were observed in the brain (0.33 and 0.17 [AUC0–2h], respectively).
CONCLUSION:
After a single oral dose of prucalopride, high concentrations were detected in the pancreas, liver and small intestine, and very low concentrations in the brain (∼0.05% of the dose in non-pregnant female rats). Mean concentrations of TR and UD in the brain were below the LOD within 24h of dosing, suggesting prucalopride is not unduly retained in the brain.
