Evaluation of In Vitro Cytochrome P450 Inhibition and In Vitro Fate of Structurally Diverse N-Oxide Metabolites: Case Studies with Clozapine, Levofloxacin, Roflumilast, Voriconazole and Zopiclone

Giri, Poonam; Naidu, Sneha; Patel, N. K.; Patel, Harilal; Srinivas, Nuggehally R.

doi:10.1007/s13318-016-0385-7

Cited by 20 publications

(12 citation statements)

References 21 publications

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“…Indeed, Giri et al reported that another N-oxide metabolite-voriconazole N-oxide-was an effective inhibitor of CYP3A4 (IC50 8.7 μM; 36), and there are other CYP-mediated drug metabolites that have been shown to be more effective inhibitors than the parent drugs. These include not only reactive metabolites generated by CYP oxidation of alkylamino, methylenedioxyphenyl, thionosulfur, phenolic, and unsaturated moieties (37-43) but also major isolable metabolites that elicit reversible inhibition of CYPs (44)(45)(46).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4

Ghassabian

Gillani

Rawling

et al. 2019

AAPS J

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The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy. In this study undertaken in hepatic microsomes from individual donors, we assessed the possibility that SNO might contribute to pharmacokinetic interactions mediated by SOR. Enzyme kinetics of CYP3A4-mediated midazolam 1′ -hydroxylation in individual human hepatic microsomes were analyzed by nonlinear regression and appropriate replots. Thus, SNO and SOR were linear-mixed inhibitors of microsomal CYP3A4 activity (Kis 15 ± 4 and 33 ± 14 μM, respectively). To assess these findings, further molecular docking studies of SOR and SNO with the 1TQN crystal structure of CYP3A4 were undertaken. SNO elicited a larger number of interactions with key amino acid residues located in substrate recognition sequences of the enzyme. In the optimal docking pose, the N-oxide moiety of SNO was also found to interact directly with the heme moiety of CYP3A4. These findings suggest that SNO could contribute to pharmacokinetic interactions involving SOR, perhaps in individuals who produce high circulating concentrations of the metabolite.

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Section: Discussionmentioning

confidence: 99%

Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4

Ghassabian

Gillani

Rawling

et al. 2019

AAPS J

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“…Notably, hemoglobin tends to be the modulator of voriconazole trough concentration. Voriconazole is primarily metabolized in the liver, and hemoglobin may be involved in the formation of its major metabolite, N-oxide voriconazole (48). Nevertherless, the mechanism of interaction remains unknown.…”

Section: Accepted Articlementioning

confidence: 99%

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

Zhao

Lin

Zhang

et al. 2020

Clinical Translational Sci

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Voriconazole is the mainstay for the treatment of invasive fungal infections in patients who underwent a kidney transplant. Variant CYP2C19 alleles, hepatic function, and concomitant medications are directly involved in the metabolism of voriconazole. However, the drug is also associated with numerous adverse events. The purpose of this study was to identify predictors of adverse events using binary logistic regression and to measure its trough concentration using multiple linear modeling. We conducted a prospective analysis of 93 kidney recipients cotreated with voriconazole and recorded 213 trough concentrations of it. Predictors of the adverse events were voriconazole trough concentration with the odds ratios (OR) of 2.614 (P = 0.016), cytochrome P450 2C19 (CYP2C19), and hemoglobin (OR 0.181, P = 0.005). The predictive power of these three factors was 91.30%. We also found that CYP2C19 phenotypes, hemoglobin, platelet count, and concomitant use of ilaprazole had quantitative relationships with voriconazole trough concentration. The fit coefficient of this regression equation was R 2 = 0.336, demonstrating that the model explained 33.60% of interindividual variability in the disposition of voriconazole. In conclusion, predictors of adverse events are CYP2C19 phenotypes, hemoglobin, and voriconazole trough concentration. Determinants of the voriconazole trough concentration were CYP2C19 phenotypes, platelet count, hemoglobin, concomitant use of ilaprazole. If we consider these factors during voriconazole use, we are likely to maximize the treatment effect and minimize adverse events. Invasive fungal infections are a feared complication in kidney transplant recipients, occurring in 0.1-3.5% of solid organ recipients. 1 Its 12-week survival rates were only 60.7%, and 22.1% of the survivors experienced graft loss because of invasive fungal infections. 2 Kidney transplantation, in conjunction with calcineurin inhibitors, is regarded as the best

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“…Previously we have executed in vitro experiments to unambiguously evaluate the role of N-oxide metabolites of diversified chemical structures such as clozapine, levofloxacin, roflumilast, voriconazole and zopiclone for the potential CYP inhibition [19]. Accordingly, it was summarized that certain N-oxide metabolites such as clozapine-N-oxide and voriconazole-N-oxide may potentially play a role as a perpetrator drug despite having a higher potency (> 1 µM but < 10 µM) for certain CYP enzymes because the N-oxide metabolites are long-lived and therefore, may potentially accumulate after multiple doses in patients who may further manifest impaired clearance of such N-oxide metabolite(s) [19].…”

Section: Discussionmentioning

confidence: 99%

“…Inhibition of CYP3A4 by ITZ, OH-ITZ, keto-ITZ, and ND-ITZ was evaluated using hydroxylation of midazolam as a probe reaction, and unbound IC 50 values were 6.1 nM, 4.6 nM, 7.0 nM, and 0.4 nM, respectively. Itraconazole metabolites are equally or more potent CYP3A4 inhibitors than parent itself, and therefore are responsible for in vitro versus in vivo discrepancy observed in CYP3A4 inhibition by ITZ [15, 16]; b) Warfarin: Hydroxywarfarin, the key metabolite showed inhibition of CYP2C9 in vitro (human liver microsomes and recombinant enzymes) [17]; c) Amiodarone: Desethylamiodarone metabolite was shown to inhibit CYP1A1, CYP1A2, CYP2B6 and CYP2D6 in vitro (human B-lymphoblastoid cell microsomes) and ex vivo (human plasma) [18]; d) Voriconazole: The voriconazole N-oxide metabolite was shown to inhibit both CYP2C9 and CYP3A4 enzyme in a competitive fashion in both human liver microsomes and hepatocytes [19]. From the ensuing topic discussed above, an independent assessment for in vitro CYP inhibition potential of metabolite(s), in addition to parent drug, may be warranted to make an informed risk assessment decision of drugs in development.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole , Aldicarb, Methiocarb, Montelukast and Ziprasidone

Giri

Gupta

Naidu

et al. 2018

DML

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Evaluation of In Vitro Cytochrome P450 Inhibition and In Vitro Fate of Structurally Diverse N-Oxide Metabolites: Case Studies with Clozapine, Levofloxacin, Roflumilast, Voriconazole and Zopiclone

Abstract: Clinical DDI potential of specific CYP enzymes needs to be considered arising due to circulatory concentrations of certain N-oxides depending on the dose size and/or frequency of dosing of the respective parent drugs.

Cited by 20 publications

References 21 publications

Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4

Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4

Predictors of Adverse Events and Determinants of the Voriconazole Trough Concentration in Kidney Transplantation Recipients

In Vitro Drug-Drug Interaction Potential of Sulfoxide and/or Sulfone Metabolites of Albendazole, Triclabendazole , Aldicarb, Methiocarb, Montelukast and Ziprasidone

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