Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes

Murayama, Norie; Imai, Naoko; Nakane, Takahisa; Shimizu, Makiko; Yamazaki, Hiroshi

doi:10.1016/j.bcp.2007.03.012

Cited by 122 publications

(130 citation statements)

References 15 publications

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“…The C max and AUC 12 of voriconazole in PMs were approximately 2.7-and 2.5-fold higher, respectively, than those in EMs ( Table 2). b Enzyme kinetic parameter inputs were mean values from in-house data (Pfizer, data on file) and published data (3,9). All other physicochemical and absorption inputs were obtained from the in-house database (Pfizer, data on file).…”

Section: Resultsmentioning

confidence: 99%

“…Fluconazole's effect on voriconazole pharmacokinetics is probably due to its inhibition of CPY2C19, since voriconazole metabolism is mainly mediated by CYP2C19, followed by CYP3A4, with CYP2C9 appearing to play only a minimal role (3,9). Omeprazole is another potent competitive inhibitor of CYP2C19 (K i , 3.1 M), but it has less of an effect on CYP3A4 (K i , 84 M) (6).…”

Section: Discussionmentioning

confidence: 99%

“…A Simcyp model for voriconazole was developed using the physicochemical properties, in vitro data, and clinical pharmacokinetic parameters obtained mainly from the inhouse database (Table 1). The recombinant enzyme kinetics inputs (maximum reaction velocity [V max ] and Michaelis-Menten constant [K m ]) were means of the values from multiple sources that included in-house data (Pfizer, data on file) and data from published literature (3,9).…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

Damle

Varma

Wood

2011

Antimicrob Agents Chemother

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

Damle

Varma

Wood

2011

Antimicrob Agents Chemother

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“…For these 73 (Table 3). [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] The mean (± S.D.) and median CYP3A5/CYP3A4 ratios of the metabolic activities in these 47 reactions were 0.69 ± 1.23 and 0.28, respectively.…”

Section: Metabolic Activity Of Cyp3a4 and Cyp3a5mentioning

confidence: 99%

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Niwa

Murayama

Yamazaki

2010

JOURNAL OF HEALTH SCIENCE

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A meta-analysis was performed on the reported literature regarding followings. First, values of the MichaelisMenten constants (K m ), maximal velocities (V max ), and intrinsic clearance (V max /K m ) and the metabolic activities mediated by human cytochrome P450 3A4 and/or 3A5; second, inhibition constants (K i ); and third, maximum inactivation rate constants (k inact ) to establish the contribution of P450 3A5 to drug metabolism. At least 120 of the 127 metabolic reactions investigated (> 94%) were catalyzed by P450 3A4 and by P450 3A5. In the 73 metabolic reactions for which data were available, the mean P450 3A5/P450 3A4 ratios of K m , V max , and V max /K m values were 1.93, 1.25, and 1.20, respectively, but the median ratios were 1.17, 0.64, and 0.56, respectively. In 14-18% of the metabolic reactions, the V max and V max /K m values for P450 3A5 were more than twice those for P450 3A4. The K i values for P450 3A5 were on average approximately 5 times those for P450 3A4. Five of 13 mechanism-based inhibitors of P450 3A4 (38%) did not exhibit similar mechanism-based inhibition of P450 3A5. These collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.

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“…VRC is metabolized into pharmacologically inactive metabolites by cytochrome P450 2C9 (CYP2C9), CYP2C19, and CYP3A4 or flavincontaining monooxygenases (FMOs) in humans (6)(7)(8). Roffey et al, however, reported that the clearance of VRC in mice and rats was enhanced after multiple administrations, suggesting the autoinduction of metabolism (5).…”

mentioning

confidence: 99%

Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

Ohbuchi

Yoshinari

Kaneko

et al. 2013

Antimicrob Agents Chemother

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The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the speciesspecific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr-and Car-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed in Pxr-null and Car-null mice but not in Pxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. Hepatic Cyp3a11 mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels of CYP3A4 and CYP2B6 (human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR-and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species.

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Roles of CYP3A4 and CYP2C19 in methyl hydroxylated and N-oxidized metabolite formation from voriconazole, a new anti-fungal agent, in human liver microsomes

Cited by 122 publications

References 15 publications

Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

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