Here is the link
Sci-Hub | Management of Drug and Food Interactions with Azole Antifungal Agents in Transplant Recipients. Pharmacotherapy, 30(8), 842–854 | 10.1592/phco.30.8.842
From the abstract: “Concomitant administration of azoles and immunosuppressive agents may cause clinically significant drug interactions resulting in extreme immunosuppression or toxicity.”
Belatedly and thanks to your question, I read the full article and realize that what this means is that azoles used together with rapamycin can drastically – up to tenfold – increase the concentration of the latter. I.e. an effect akin to grapefruit juice, which some of us use to reduce the dose of rapamycin. Table 3 in the article shows that the sirolimus dose should be reduced by 90 % for two of the azole drugs.
From the article:
“Drug interaction–related toxicities occur mainly as a result of increased concentrations of the coadministered drug, such as an immunosuppressant,because of inhibition of its metabolism by the azole”
“Perhaps the most clinically significant drug interactions observed with azoles in the transplant recipient occur with concomitantly administered immunosuppressive agents”.
“Specifically, immunosuppressants that require dosage adjustment and close monitoring for toxicity include the calcineurin inhibitors, cyclosporine and tacrolimus, and the mammalian target of rapamycin inhibitor, sirolimus. All azole antifungals inhibit the metabolism of cyclosporine, tacrolimus, and sirolimus, which are significantly metabolized by CYP3A4. These immunosuppressants also are substrates and inhibitors of Pglycoprotein. Inhibition of both CYP3A4 and Pglycoprotein leads to increased blood concentrations of the immunosuppressants and contributes to an increased potential for adverse events because of excessive immunosuppression and toxicity (e.g., nephrotoxicity, neurotoxicity).
However, as has been shown with CYP3A4 inhibition with certain calcium channel blockers,this interaction could be beneficial by reducing the amount of immunosuppressant required to achieve therapeutic concentrations”.
BUT fenbendazole, like its cousin meant for humans mebendazole, is an anti-helmintic/worm drug not anti-fungal. Related, but with differences. The drug interaction in particular occurs with azoles that are strong inhibitors of CYP3A4 and Pglycoprotein:
RAPAMUNE®Drug Interactions (sirolimus) | Pfizer Medical Information - US
Mebendazole, and presumably Fenbendazole, is classified as a weak inhibitor of CYP3A4. This should mean that the interaction of Fenben with rapamycin should not be so strong.
Still, my lymphocytes dropped like a stone when taking rapa+fenben. Not sure what to make of this.
