<p>Drug&ndash;drug interaction study of imatinib and voriconazole in vitro and in vivo</p>

Abstract

Background: In clinical practice, common problem polypharmacy could result in the increased risks of drug–drug interactions (DDIs). Co-administered imatinib (IMA) and voriconazole (VOR) as one treatment protocol in cancer patients with fungal infections are common. Purpose: The aim of the present study was to assess the potential DDIs associated with the concurrent use of IMA and VOR in rat liver microsomes (RLMs) and in rats. Methods and results: The concentration levels of IMA, VOR, and their metabolites N-desmethyl IMA (CGP74588) and N-oxide voriconazole (N-oxide VOR) were determined by ultra performance liquid chromatography-tandem mass spectrometry. In vitro study of RLMs, VOR inhibited the IMA metabolism with the half-maximal inhibitory concentration (IC 50 ) of 105.20 μM, while IC 50 for IMA against VOR was 61.30 μM. After co-administered IMA and VOR in rats, the C max of IMA was increased significantly, while the AUC 0→t , AUC 0→∞ , and C max of CGP74588 were decreased significantly. In addition, similar results were also found that the main pharmacokinetic parameters (AUC 0→t , AUC 0→∞ , MRT 0→∞ , T max, and C max ) of VOR were increased significantly, while the AUC 0→t , AUC 0→∞ , and C max of N-oxide VOR were decreased significantly. Incorporation of all the results indicated that both drugs had a inhibitory effect on each other’s metabolism in vitro and in vivo. Conclusion: Thus, it is of great value to monitor the concomitant use of IMA and VOR in the clinic to reduce the risks of unexpected clinical outcomes.

The Overview on the Pharmacokinetic and Pharmacodynamic Interactions of Triazoles

“…Antifungal drugs are commonly used during the treatment of tumors. The therapy of chronic myeloid leukemia and gastrointestinal stromal tumors often requires antifungal agents against invasive aspergillosis [61]. There are several studies in which the voriconazole effect on imatinib has been studied.…”

Factors Influencing the Steady-State Plasma Concentration of Imatinib Mesylate in Patients With Gastrointestinal Stromal Tumors and Chronic Myeloid Leukemia

“…IM is a well-known, orally administered tyrosine kinase inhibitor (TKI) ( Musumeci et al, 2015 ). The bioavailability of IM is ∼90% via the oral route, as it is metabolized predominantly by cytochrome P450 enzymes ( Musumeci et al, 2015 ), CYP3A4 ( Maddin et al, 2016 ), and CYP3A5 ( Cargnin et al, 2018 ), to its major circulating active metabolite, N -desmethyl imatinib (NDI)/CGP74588 ( Lin et al, 2019 ). This metabolite also binds to the ATP binding pocket of the tyrosine kinase domain ( Josephs et al, 2013 ).…”

<p>Effects of Dexmedetomidine on the Pharmacokinetics of Dezocine, Midazolam and Its Metabolite 1-Hydroxymidazolam in Beagles by UPLC-MS/MS</p>

“…DEX is a highly selective α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic and analgosedative properties. 1 DEX is metabolised by glucuronidation and CYP2A6 hydroxylation and subsequently excreted in urine almost exclusively as a metabolite. 4,5 DEX is a strong inhibitor of cytochrome CYP450 enzyme.…”

“…In clinical practice, polypharmacy is a common problem and results in the increased risks of DDIs. 1 Ultimately, taking multiple medications simultaneously increases an individual's risk for undesirable DDIs that lead to serious and debilitating adverse drug reactions (ADRs). 2 A primary reason of DDIs is the change of the cytochrome P450 (CYP450) isozyme activity by inducing or inhibiting.…”