Why is the rectal route for NSAIDS favorable for preventing post-ERCP pancreatitis?

Acute pancreatitis is a frequent, burdensome adverse event of endoscopic retrograde cholangiography (ERCP). Rectal nonsteroidal anti-inflammatory drugs (NSAIDs) have reduced post-ERCP pancreatitis (PEP) risk by about 50 % and show greater efficacy over parenteral or oral administration, although the mechanism for its superiority remains unclear. To probe this question, we investigated in a preclinical model, the pharmacokinetics in the blood, pancreas and other tissues of the NSAID diclofenac given via the rectal, intravenous, or intragastric routes.

The data on diclofenac was extracted from a larger study that examined a combination of diclofenac and tacrolimus. 20.8 mg diclofenac/kg body weight, which is the mouse equivalent dosing used in clinical practice for PEP prophylaxis, was administered to C57BL/6J mice via the rectal, intravenous and intragastric (oral) routes. Cross-collection of blood and tissues was done at various timepoints after administration for the evaluation of drug levels and pharmacokinetic parameters.

Rectal diclofenac demonstrated favorable blood pharmacokinetics and systemic bioavailability as well as sustained pancreas penetration. The total pancreas exposure to diclofenac over 24 h following rectal dosing was not significantly different as compared to intravenous and oral dosing.

Our findings suggest that the efficacy of rectal diclofenac in PEP prevention relates more to its higher and consistent systemic exposure than its absolute pancreas levels. The implications are that the rectal route provides both systemic and pancreas exposure for the full duration of PEP vulnerability.