Effect of itraconazole on the pharmacokinetics of everolimus administered by different routes in rats

Abstract

The effect of itraconazole on the pharmacokinetics of everolimus was investigated in rats. Ten minutes after an intravenous or intraintestinal administration of itraconazole, everolimus was delivered intravenously (0.2 mg/kg) or intraintestinally (0.5 mg/kg). Blood concentrations of everolimus were measured up to 240 min, and pharmacokinetic parameters were calculated. Intraintestinally administered itraconazole (20 mg/kg) significantly increased the area under the concentration-time curve (AUC) of intraintestinally administered everolimus about 4.5-fold, but even at 50 mg/kg did not affect the AUC of intravenously administered everolimus. However, intravenously administered itraconazole (50 mg/kg) increased the AUC of both intraintestinally and intravenously administered everolimus approximately 2-fold. Using a value for hepatic blood flow from the literature (50 ml/min/kg), the apparent intestinal and hepatic extraction of everolimus without itraconazole was calculated as about 80% and 13%, respectively. Intraintestinally administered itraconazole (20 mg/kg) changed the apparent intestinal extraction by 0.26-fold from 0.829 to 0.215, but the hepatic availability of everolimus was almost unchanged after the intravenous or intraintestinal administration of itraconazole even at a dose of 50 mg/kg from 0.871 to 0.923 or 0.867, respectively. In conclusion, intraintestinally administered itraconazole dramatically increased the AUC of everolimus delivered intraintestinally by inhibiting the intestinal first-pass extraction of this drug.

Subcutaneous phaeohyphomycosis caused by Pleurostomophora richardsiae in a renal transplant recipient

“…The patient's infection recurred after excision, suggesting that combined surgical and medical therapy may be required to completely eradicate P richardsiae . Importantly, itraconazole, a direct cytochrome P450 3A4 inhibitor, can increase serum levels of calcineurin inhibitors and mammalian target of rapamycin inhibitors, such as everolimus in this patient 7 . Therefore, initiation of antifungal therapy often necessitates the reduction in the dosages of immunosuppressant therapies in transplant recipients.…”

Everolimus, a mammalian target of rapamycin inhibitor, ameliorated streptozotocin-induced learning and memory deficits via neurochemical alterations in male rats

“…Our findings revealed that short-term treatment with a high dose of EVR (5 mg/kg for 7 days on days 21-28 post STZ injection when the learning and memory impairments were established) or chronic administration of low (1 mg/kg) or high (5 mg/kg) doses of EVR from day 0 (day of STZ icv injection) to day 20, were able to attenuate STZ-induced learning and memory deficits by inhibiting oxidative stress, amelioration of neuronal injury, and restoration of AChE activity in the hippocampus. The doses and time schedule of the administration of EVR were selected based on preliminary experiments, as well as, previous studies (Russo et al, 2016[ 65 ]; Sanchez-Fructuoso, 2008[ 68 ]; Yokomasu et al, 2009[ 90 ]).…”