Further studies on the dissociation of the isosafrole metabolite-cytochrome p-450 complex

Dickins, Maurice; Elcombe, Clifford R.; Moloney, Stephen J.; Netter, K.J.; Bridges, James W.

doi:10.1016/0006-2952(79)90509-4

Cited by 58 publications

(19 citation statements)

References 24 publications

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“…20–23 Elcombe and coworkers 24 observed type III interaction in rat hepatic microsomes treated with isosafrole, which in a further study they attributed to a stable ferrocytochrome:carbene complex (Fe 2+ :carbene). 25 The 425/455 nm absorbance is considered the defining characteristic of MIC formation. 26 An additional hypothesis reported by several authors is that the 425–427 nm peak is due to the carbine-induced displacement of the axial thiolate, leading to irreversible enzyme inactivation.…”

Section: Introductionmentioning

confidence: 99%

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Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

et al. 2016

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An in vitro observation of time-dependent-inhibition of metabolic enzymes often results in removing a potential drug from the drug-pipeline. However, the accepted method for predicting TDIs of the important drug metabolizing cytochrome P450 enzymes often overestimates the drug interaction potential. Better models that take into account the complexities of the cytochrome P450 enzyme system will lead to better predictions. Herein we report the use of our previously described models for complex kinetics of podophyllotoxin. Spectral characterization of the kinetics indicates that an intermediate MI-complex is formed, which slowly progresses to an essentially irreversible MI-complex. The intermediate MI-complex can release free enzyme during the time-course of a typical 30 minute TDI experiment. This slow rate of MI-complex conversion results in an over-prediction of the kinact value if this process is not included in the analysis of the activity versus time profile. In vitro kinetic experiments in rat liver microsomes predicted a lack of drug interaction between podophyllotoxin and midazolam. In vivo rat pharmacokinetic studies confirmed this lack of drug interaction.

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Section: Introductionmentioning

confidence: 99%

“…2, 27 Moreover, an additional peak at 438 nm was identified and attributed to a supposed oxidized cytochrome P450-metabolite (Fe 3+ :carbene). 25 …”

Section: Introductionmentioning

confidence: 99%

Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

et al. 2016

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“…For quasi-irreversible inactivation due to MIC formation, the in vitro data are consistent with reversibility within the incubation time frame. Observations that corroborate in vitro reversibility include removal of nitroso-derived MICs and restoration of enzymatic activity by dialysis (Ma et al, 2000) and displacement of methylenedioxyphenyl complexes with hydrophobic substrates (Dickins et al, 1979). However, it is unknown whether and to what extent reversible events occur in vivo.…”

Section: Discussionmentioning

confidence: 96%

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

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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.

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“…The NADPH-dependence of complex formation indicated that oxidative metabolism of I is required. Based on previous mech- anistic studies of P450 complex formation with isosafrole, another lipophilic methylenedioxyphenyl compound, the formation of a P450-metabolite complex with I may involve oxidation of the methylenedioxy bridge carbon of ABT-200, possibly through a carbene intermediate, which then binds to the heme iron of P450 forming a complex as proposed by Dickins et al (1979).…”

Section: Discussionmentioning

confidence: 96%

“…Treatment of rats with isosafrole followed by isolation of hepatic microsomes results in the formation of a P450-metabolite complex, which exhibits absorption maxima at 455 nm in the dithionite-reduced difference spectrum (type III spectra) (Franklin, 1971). Formation of these complexes is believed to occur by NADPH-dependent oxidation of the methylenedioxy ring to yield a carbene and is accompanied by the inhibition of monooxygenase activity (Ullrich, 1977;Dickins et al, 1979;Mansuy, 1980). The objective of these studies was to evaluate the metabolic fate of I in the dog and the potential relationship between metabolism and the nonlinear pharmacokinetic behavior.…”

Section: ) Is a Novel Pyrrolidine Derivative That Exists As A Racemicmentioning

confidence: 99%

Implication of P450-Metabolite Complex Formation in the Nonlinear Pharmacokinetics and Metabolic Fate of (±)-(1′R,3R)-3-Phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylene-dioxy-1′-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in Dogs

Thomas¹,

Marsh²,

Rodrigues³

et al. 2002

Drug Metab Dispos

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Following a single oral or intravenous administration of the R,R(؉) and S,S(؊)14 C-pseudoracemate of (؎)-(1R*,3R*)-3-phenyl-1- [(1,2,3,4-tetrahydro-5,6-methylene-dioxy-1-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200/I) to dogs, a total of six (R,R[؉]) and eight (S,S[؊]) metabolites were identified by highpressure liquid chromatography/mass spectral techniques. Greater than 99% of the dose was eliminated as metabolites indicating that the clearance of I was predominantly metabolic. The catechol was the major excreted metabolite (fecal), whereas the urine and bile predominantly contained metabolites resulting from secondary biotransformation of the catechol via O-methylation, glucuronidation, and sulfation. After a single 12 mg/kg oral dose of racemic I to dogs, the mean area under the plasma curve (AUC 0-24h ) averaged 4.55 g ⅐ h/ml, with an apparent plasma clearance value of 2.70 l/h ⅐ kg. After 14 daily doses, the apparent plasma clearance was 3.5-fold lower (0.78 l/h ⅐ kg) and the AUC 0-24h about 4-fold higher (18.58 g ⅐ h/ml). Isolation of liver microsomes from these animals indicated that a cytochrome P450 (P450)-metabolite complex (MI complex) was formed in the liver after both single and multiple dosing. The mean concentration of the MI complex 24 h after a single dose averaged 31 pmol/mg of microsomal protein, whereas the amount in the animals given multiple doses of I averaged 163 pmol/mg. There was a positive correlation (R 2 ‫؍‬ 0.993) between the plasma AUC for I and the amount of the MI complex found in the liver of each animal. Formation of the MI complex was demonstrated in vitro in control dog liver microsomes, was NADPH-dependent, and was dissociated from P450 with 2-methylbenzimidazole. In vitro preincubation studies indicated that I was a mechanism-based inhibitor and that formation of the complex inhibited catechol formation. These results demonstrate that the liver P450s that metabolize I form an inhibitory MI complex after in vivo administration in dogs. Formation of the complex increases during multiple dosing and inhibits the enzymes from further metabolism of I resulting in nonlinear pharmacokinetics.ABT-200 1 (I; Fig. 1 ) is a novel pyrrolidine derivative that exists as a racemic mixture of the S,S(Ϫ)-and R,R(ϩ)-enantiomers.Preliminary studies demonstrated that the compound exhibited nonlinear pharmacokinetics during oral administration in the dog. Whereas initial studies with dog and human liver microsomes generated only the NADPH-dependent catechol metabolite of I, liver slices from these species formed extensive amounts of secondary metabolites resulting from further biotransformation of the catechol derivative via O-methylation, sulfation, and glucuronidation (Ferrero et al., 1997).These results suggested that oxidation of the methylenedioxy bridge carbon to form the catechol was a major initial metabolic step in the metabolism of I.Certain methylenedioxyphenyl compounds interact with the mixedfunction oxidases to form metabolite complexes with cytochrome P450...

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Further studies on the dissociation of the isosafrole metabolite-cytochrome p-450 complex

Cited by 58 publications

References 24 publications

Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

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

Implication of P450-Metabolite Complex Formation in the Nonlinear Pharmacokinetics and Metabolic Fate of (±)-(1′R,3R)-3-Phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylene-dioxy-1′-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in Dogs

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Further studies on the dissociation of the isosafrole metabolite-cytochrome p-450 complex

Cited by 58 publications

References 24 publications

Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

Mechanism-Based Inhibition of CYP3A4 by Podophyllotoxin: Aging of an Intermediate Is Important for in Vitro/in Vivo Correlations

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

Implication of P450-Metabolite Complex Formation in the Nonlinear Pharmacokinetics and Metabolic Fate of (±)-(1′R*,3R*)-3-Phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylene-dioxy-1′-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in Dogs

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Implication of P450-Metabolite Complex Formation in the Nonlinear Pharmacokinetics and Metabolic Fate of (±)-(1′R,3R)-3-Phenyl-1-[(1′,2′,3′,4′-tetrahydro-5′,6′-methylene-dioxy-1′-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in Dogs