The Experts below are selected from a list of 14517 Experts worldwide ranked by ideXlab platform
Zeruesenay Desta - One of the best experts on this subject based on the ideXlab platform.
-
comprehensive in vitro analysis of Voriconazole inhibition of eight cytochrome p450 cyp enzymes major effect on cyps 2b6 2c9 2c19 and 3a
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Seong Wook Jeong, Phuong D Nguyen, Zeruesenay DestaAbstract:Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of Voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of Voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, Voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 microM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 microM Voriconazole). Further detailed experiments with HLMs showed that Voriconazole is a potent competitive inhibitor of CYP2B6 (K(i) < 0.5), CYP2C9 (K(i) = 2.79 microM), and CYP2C19 (K(i) = 5.1 microM). The inhibition of CYP3A by Voriconazole was explained by noncompetitive (K(i) = 2.97 microM) and competitive (K(i) = 0.66 microM) modes of inhibition. Prediction of the in vivo interaction of Voriconazole from these in vitro data suggests that Voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.
-
comprehensive in vitro analysis of Voriconazole inhibition of eight cytochrome p450 cyp enzymes major effect on cyps 2b6 2c9 2c19 and 3a
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Seong Wook Jeong, Phuong D Nguyen, Zeruesenay DestaAbstract:Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of Voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of Voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, Voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, K i K i = 2.79 μM), and CYP2C19 ( K i = 5.1 μM). The inhibition of CYP3A by Voriconazole was explained by noncompetitive ( K i = 2.97 μM) and competitive ( K i = 0.66 μM) modes of inhibition. Prediction of the in vivo interaction of Voriconazole from these in vitro data suggests that Voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.
Seong Wook Jeong - One of the best experts on this subject based on the ideXlab platform.
-
comprehensive in vitro analysis of Voriconazole inhibition of eight cytochrome p450 cyp enzymes major effect on cyps 2b6 2c9 2c19 and 3a
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Seong Wook Jeong, Phuong D Nguyen, Zeruesenay DestaAbstract:Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of Voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of Voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, Voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 microM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 microM Voriconazole). Further detailed experiments with HLMs showed that Voriconazole is a potent competitive inhibitor of CYP2B6 (K(i) < 0.5), CYP2C9 (K(i) = 2.79 microM), and CYP2C19 (K(i) = 5.1 microM). The inhibition of CYP3A by Voriconazole was explained by noncompetitive (K(i) = 2.97 microM) and competitive (K(i) = 0.66 microM) modes of inhibition. Prediction of the in vivo interaction of Voriconazole from these in vitro data suggests that Voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.
-
comprehensive in vitro analysis of Voriconazole inhibition of eight cytochrome p450 cyp enzymes major effect on cyps 2b6 2c9 2c19 and 3a
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Seong Wook Jeong, Phuong D Nguyen, Zeruesenay DestaAbstract:Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of Voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of Voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, Voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, K i K i = 2.79 μM), and CYP2C19 ( K i = 5.1 μM). The inhibition of CYP3A by Voriconazole was explained by noncompetitive ( K i = 2.97 μM) and competitive ( K i = 0.66 μM) modes of inhibition. Prediction of the in vivo interaction of Voriconazole from these in vitro data suggests that Voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.
Phuong D Nguyen - One of the best experts on this subject based on the ideXlab platform.
-
comprehensive in vitro analysis of Voriconazole inhibition of eight cytochrome p450 cyp enzymes major effect on cyps 2b6 2c9 2c19 and 3a
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Seong Wook Jeong, Phuong D Nguyen, Zeruesenay DestaAbstract:Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of Voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of Voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, Voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, <6 microM); its effect on CYP1A2, CYP2A6, CYP2C8, and CYP2D6 was marginal (<25% inhibition at 100 microM Voriconazole). Further detailed experiments with HLMs showed that Voriconazole is a potent competitive inhibitor of CYP2B6 (K(i) < 0.5), CYP2C9 (K(i) = 2.79 microM), and CYP2C19 (K(i) = 5.1 microM). The inhibition of CYP3A by Voriconazole was explained by noncompetitive (K(i) = 2.97 microM) and competitive (K(i) = 0.66 microM) modes of inhibition. Prediction of the in vivo interaction of Voriconazole from these in vitro data suggests that Voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.
-
comprehensive in vitro analysis of Voriconazole inhibition of eight cytochrome p450 cyp enzymes major effect on cyps 2b6 2c9 2c19 and 3a
Antimicrobial Agents and Chemotherapy, 2009Co-Authors: Seong Wook Jeong, Phuong D Nguyen, Zeruesenay DestaAbstract:Voriconazole is an effective antifungal drug, but adverse drug-drug interactions associated with its use are of major clinical concern. To identify the mechanisms of these interactions, we tested the inhibitory potency of Voriconazole with eight human cytochrome P450 (CYP) enzymes. Isoform-specific probes were incubated with human liver microsomes (HLMs) (or expressed CYPs) and cofactors in the absence and the presence of Voriconazole. Preincubation experiments were performed to test mechanism-based inactivation. In pilot experiments, Voriconazole showed inhibition of CYP2B6, CYP2C9, CYP2C19, and CYP3A (half-maximal [50%] inhibitory concentrations, K i K i = 2.79 μM), and CYP2C19 ( K i = 5.1 μM). The inhibition of CYP3A by Voriconazole was explained by noncompetitive ( K i = 2.97 μM) and competitive ( K i = 0.66 μM) modes of inhibition. Prediction of the in vivo interaction of Voriconazole from these in vitro data suggests that Voriconazole would substantially increase the exposure of drugs metabolized by CYP2B6, CYP2C9, CYP2C19, and CYP3A. Clinicians should be aware of these interactions and monitor patients for adverse effects or failure of therapy.
Steven Trifilio - One of the best experts on this subject based on the ideXlab platform.
-
breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic Voriconazole
Bone Marrow Transplantation, 2007Co-Authors: Steven Trifilio, S Singhal, S Williams, Olga Frankfurt, Leo I Gordon, Andrew M Evens, Jane N Winter, Martin S Tallman, Jayesh MehtaAbstract:Seventy-one allograft recipients receiving Voriconazole, in whom complete clinical, microbiologic and pharmacokinetic data were available, were studied to determine the efficacy of Voriconazole in preventing fungal infections. The length of Voriconazole therapy was 6-956 days (median 133). The total number of patient-days on Voriconazole was 13 805 ( approximately 38 years). A total of 10 fungal infections were seen in patients on Voriconazole (18% actuarial probability at 1 year): Candida glabrata (n=5), Candida krusei (n=1), Cunninghamella (n=1), Rhizopus (n=2) and Mucor (n=1). Two of the four zygomycosis cases were preceded by short durations of Voriconazole therapy, but prolonged itraconazole prophylaxis. The plasma steady-state trough Voriconazole levels around the time the infection occurred were 2 microg/ml (P=0.061). We conclude that Voriconazole is effective at preventing aspergillosis. However, breakthrough zygomycosis is seen in a small proportion of patients. The role of therapeutic Voriconazole monitoring with dose adjustment to avoid breakthrough infections with fungi that are otherwise susceptible to the drug needs to be explored prospectively.
-
breakthrough zygomycosis after Voriconazole administration among patients with hematologic malignancies who receive hematopoietic stem cell transplants or intensive chemotherapy
Bone Marrow Transplantation, 2007Co-Authors: Steven Trifilio, Charles L Bennett, Paul R Yarnold, June M Mckoy, Jorge P Parada, Jayesh Mehta, G Chamilos, Frank Joseph Palella, Leanne Kennedy, Kathleen M MullaneAbstract:Zygomycosis is increasingly reported as a cause of life-threatening fungal infections. A higher proportion of cases reported over the last decades have been in cancer patients, with or without hematopoietic stem cell transplantation (HSCT). The new anti-fungal agent Voriconazole is a recently identified risk factor for developing zygomycosis. We reviewed the clinical characteristics and outcomes of a large cohort of cancer patients who developed zygomycosis after exposure to Voriconazole. Health care professionals at 13 large cancer centers provided clinical information on cancer patients with zygomycosis and prior exposure to Voriconazole. Criteria for inclusion were 5 days or more of Voriconazole use and diagnostic confirmation with tissue or histology. Fifty-eight cases were identified among patients with hematologic malignancies, 62% including patients who underwent a HSCT procedure. Fifty-six patients received Voriconazole for primary or secondary prophylaxis against fungal infection. In addition to prior exposure to Voriconazole, patients also had several of the previously established risk factors for zygomycosis. Amphotericin B was the most commonly prescribed anti-fungal therapy. Overall mortality was 73%. We conclude that zygomycosis after exposure to Voriconazole is a recently described entity that is frequently fatal, despite treatment with currently available anti-fungal agents and surgery.
-
Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients
Bone Marrow Transplantation, 2005Co-Authors: Steven Trifilio, R Ortiz, Gennethel Pennick, Amit Verma, Valentina Stosor, Teresa R Zembower, J MehtaAbstract:Voriconazole, a new antifungal agent, is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in Voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize Voriconazole poorly resulting in increased plasma drug levels. The clinical significance of this is unknown, and the utility of monitoring Voriconazole levels is unclear. Steady-state trough plasma Voriconazole levels were obtained in 25 allogeneic HSCT recipients using an HPLC assay. Patients had drug levels checked once (n=13), twice (n=10), or > or =3 times (n=2) 5-18 days (median 10) after starting Voriconazole or dose modification. The 41 Voriconazole levels were 0.2-6.8 microg/ml (median 1.6); 6 (15%) were <0.5 (possibly below the in vitro MIC90 for Aspergillus spp.). Voriconazole concentrations correlated with aspartate aminotranferase (AST) (r=0.5; P=0.0009) and alkaline phosphatase (r=0.34; P=0.03), but not with creatinine, bilirubin and alanine aminotransferase (ALT). Since liver dysfunction is common after HSCT, it was not possible to determine if elevated AST and alkaline phosphatase levels were the cause or the consequence of higher Voriconazole levels. We conclude that trough Voriconazole levels vary considerably between patients, and suggest monitoring levels in patients receiving Voriconazole for confirmed fungal infections, and in those with elevated AST or alkaline phosphatase levels.
Shinichiro Okamoto - One of the best experts on this subject based on the ideXlab platform.
-
impact of cytochrome p450 2c19 polymorphisms on the pharmacokinetics of tacrolimus when coadministered with Voriconazole
The Journal of Clinical Pharmacology, 2016Co-Authors: Chiyo K Imamura, Kenichi Furihata, Shinichiro Okamoto, Yusuke TanigawaraAbstract:This study evaluated the effects of cytochrome P450 (CYP) 2C19 polymorphisms on tacrolimus pharmacokinetics when coadministered with Voriconazole. Eighteen healthy volunteers, including 6 individuals in each CYP2C19 genotype (extensive metabolizers [EMs], intermediate metabolizers [IMs], and poor metabolizers [PMs]), received a single oral dose of 3 mg tacrolimus alone or in combination with 200 mg Voriconazole twice daily at steady state. When tacrolimus was coadministered with Voriconazole, a significant increase in area under its concentration-time curve (AUC0-24) was observed for all genotypes. AUC0-12 of Voriconazole in IMs and PMs were significantly higher than that in EMs (P < .05 and P < .01, respectively). Consequently, AUC0-24 of tacrolimus in combination with Voriconazole in IMs and PMs were also significantly higher than that in EMs (P < .05). These results demonstrate that CYP2C19 genotypes influenced the exposure of tacrolimus when coadministered with Voriconazole, although tacrolimus is mainly metabolized by CYP3A.
-
drug interaction between Voriconazole and tacrolimus and its association with the bioavailability of oral Voriconazole in recipients of allogeneic hematopoietic stem cell transplantation
International Journal of Hematology, 2012Co-Authors: Takehiko Mori, Jun Kato, Akiko Yamane, Masatoshi Sakurai, Sumiko Kohashi, Taku Kikuchi, Yukako Ono, Shinichiro OkamotoAbstract:In a previous study, we noted wide inter-individual variability in drug interactions between Voriconazole and tacrolimus, but that analysis did not take into account the routes of administration. In the present study, we analyzed interactions between these two drugs when both agents were administered orally after allogeneic hematopoietic stem cell transplantation (HSCT); the effect of plasma Voriconazole levels on the magnitude of the drug interaction was also examined. Twenty-five allogeneic HSCT recipients were evaluated. Trough concentrations of tacrolimus were measured prior to, and periodically for 7–10 days after, initiating Voriconazole (400 mg/day) to determine the concentration/dose (C/D) ratio of tacrolimus. The median C/D ratio of tacrolimus increased significantly from 172.8 (range 28.6–1110.7) to 537.5 (range 127.8–1933.3) (ng/mL)/(mg/kg) (P < 0.01) following initiation of Voriconazole; the median increase was 138.8 % (range −32.0 to 685.7 %). The plasma concentration of Voriconazole did not correlate with the increase of the tacrolimus C/D ratio (ρ = 0.16, P = 0.44). These results indicate that oral Voriconazole has a significant drug interaction with oral tacrolimus with a wide inter-individual variability, which cannot be explained by the bioavailability of Voriconazole. Other possible mechanisms should be explored in future studies.
