Sequential Metabolism of Secondary Alkyl Amines to Metabolic-Intermediate Complexes: Opposing Roles for the Secondary Hydroxylamine and Primary Amine Metabolites of Desipramine, (<i>S</i>)-Fluoxetine, and <i>N-</i>Desmethyldiltiazem

Hanson, Kelsey L.; VandenBrink, Brooke M.; Babu, K. Ganesh; Allen, Kyle E.; Nelson, Wendel L.; Kunze, Kent L.

doi:10.1124/dmd.110.032391

Cited by 39 publications

(50 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are two major mechanisms by which a compound exhibits mechanism-based inactivation of P450 enzymes: oxidative metabolism can lead to a reactive intermediate capable of alkylating either the protein or prosthetic heme group, or alternatively if the inhibitor structure contains an amine functional group, N-oxidation can then lead to the formation of an irreversible MI complex between a nitroso group and the heme iron (Hanson et al, 2010;VandenBrink and Isoherranen, 2010). Although there are literature data that point to the ability of AMIO to form at least trace amounts of a reactive o-quinone metabolite in rat liver microsomes, feces, and urine, the o-quinone was not detected as a circulating metabolite in plasma (Ramesh Varkhede et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Oxidative metabolism of primary and secondary amines by P450 enzymes can sometimes lead to TDI of those P450s via the formation of MI complexes. These complexes are believed to arise through the irreversible coordination of a nitrosoamine metabolite to the heme iron, within the P450 active site, and they exhibit a signature Soret absorbance maximum at around 455 nm by difference spectroscopy (Hanson et al, 2010).…”

mentioning

confidence: 99%

See 1 more Smart Citation

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

McDonald

Rettie

2015

Drug Metab Dispos

View full text Add to dashboard Cite

In this study, IC 50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I] u /K i,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (K I = 0.46 mM, k inact = 0.030 minute 21 ), while MDEA was a moderate inactivator of both CYP2D6 (K I = 2.7 mM, k inact = 0.018 minute 21) and CYP3A4 (K I = 2.6 mM, k inact = 0.016 minute 21). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex.Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

McDonald

Rettie

2015

Drug Metab Dispos

View full text Add to dashboard Cite

show abstract

“…There has been consideration of the processivity of the overall reaction (19 -23, 26) as in the case of numerous other P450 reactions (4,(61)(62)(63)(64)(65)(66). In this case, we were able to address the processivity of the zebrafish P450 17A1 reactions using several kinetic approaches.…”

Section: Discussionmentioning

confidence: 99%

Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2

Pallan

Nagy

Lei

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Fish (and human) P450 17A1 catalyze both steroid 17␣-hydroxylation and 17␣,20-lyase reactions. A second fish P450, 17A2 (51% identical), catalyzes only 17␣-hydroxylation. Results: Crystal structures of zebrafish P450 17A1 and 17A2 and human P450 17A1 are very similar. Conclusion: In kinetic analysis, the two-step oxidation of progesterone is more distributive than for pregnenolone. Significance: Small structural differences are associated with activities of the two fish P450s.

show abstract

“…For TDI experiments, it is likely that an ESI complex can be formed and could result in complex kinetics ranging from inhibition to activation. Another complexity outside the scope of this manuscript is sequential metabolism leading to TDI (Hanson et al, 2010), which, when kinetically discernible, results in concave downward PRA plots (data not shown).…”

Section: Discussionmentioning

confidence: 99%

A Numerical Method for Analysis of In Vitro Time-Dependent Inhibition Data. Part 2. Application to Experimental Data

Korzekwa¹,

Tweedie²,

Argikar³

et al. 2014

Drug Metab Dispos

View full text Add to dashboard Cite

Time-dependent inhibition (TDI) of cytochrome P450 enzymes is an important cause of drug-drug interactions. The standard approach to characterize the kinetics of TDI is to determine the rate of enzyme loss, k obs , at various inhibitor concentrations, [I], and replot the k obs versus [I] to obtain the key kinetic parameters, K I and k inact . In our companion manuscript (Part 1; Nagar et al., 2014) in this issue of Drug Metabolism and Disposition, we used simulated datasets to develop and test a new numerical method to analyze in vitro TDI data. Here, we have applied this numerical method to five TDI datasets. Experimental datasets include the inactivation of CYP2B6, CYP2C8, and CYP3A4. None of the datasets exhibited Michaelis-Menten-only kinetics, and the numerical method allowed use of more complex models to fit each dataset. Quasi-irreversible as well as partial inhibition kinetics were observed and parameterized. Three datasets required the use of a multiple-inhibitor binding model. The mechanistic and clinical implications provided by these analyses are discussed. Together with the results in Part 1, we have developed and applied a new numerical method for analysis of in vitro TDI data. This method appears to be generally applicable to model in vitro TDI data with atypical and complex kinetic schemes.

show abstract

Sequential Metabolism of Secondary Alkyl Amines to Metabolic-Intermediate Complexes: Opposing Roles for the Secondary Hydroxylamine and Primary Amine Metabolites of Desipramine, (S)-Fluoxetine, and N-Desmethyldiltiazem

Abstract: Three secondary amines desipramine (DES), (S)-fluoxetine [(S)-

Cited by 39 publications

References 31 publications

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms

Structural and Kinetic Basis of Steroid 17α,20-Lyase Activity in Teleost Fish Cytochrome P450 17A1 and Its Absence in Cytochrome P450 17A2

A Numerical Method for Analysis of In Vitro Time-Dependent Inhibition Data. Part 2. Application to Experimental Data

Contact Info

Product

Resources

About