Pharmacokinetics of fentanyl after dermal administration to arthritis model rats

[Speaker] Tsutomu Shimada:1
[Co-author] Akari Maeda:1, Gaku Akashita:1, Yoshimichi Sai:1
1:Department of Hospital Pharmacy, University Hospital, Kanazawa University, Japan

Fentanyl transdermal delivery patches are used to control not only cancer pain, but also chronic pain, such as that due to osteoarthritis or post-herpetic neuralgia, but there are inter-individual differences in its efficacy. To clarify the contribution of inflammation to these differences, we investigated the pharmacokinetics of fentanyl in arthritis model rats treated with transdermal patches.

Adjuvant arthritis model rats (AA) were produced by injection of complete Freund's adjuvant into the base of the tail of Lewis rats. After 21 days, fentanyl was administered intravenously (10 μg/kg) or transdermally (0.25 mg/body). Blood was sampled at designated times, and the concentrations of fentanyl and norfentanyl (an inactive metabolite) in plasma were determined by LC/MS.

Body weight and fat weight of AA rats were significantly decreased compared to the control values. After intravenous administration, the concentrations of fentanyl and norfentanyl in AA rats were comparable to those in controls, but the distribution volume at the steady state (Vdss) was significantly decreased in the AA rats. After transdermal administration, the norfentanyl concentration and metabolic ratio (MR; AUC of norfentanyl / AUC of fentanyl) were significantly increased in AA rats, even through the dose of fentanyl per body weight was low and the release ratio from the patch in AA rats was unchanged.

The intravenous study indicated that arthritis did not influence fentanyl concentration, although fentanyl distribution decreased in parallel with the body fat decrease in AA rats. After transdermal administration, the dose-adjusted fentanyl concentration was significantly decreased in AA rats, indicating that the skin contributes to fentanyl metabolism, and that arthritic status is one of the factors contributing to inter-individual differences in fentanyl concentration, when fentanyl is administered via a transdermal delivery patch.

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