The Enzymic Formation of a Methylenedioxyphenyl Derivative Exhibiting an Isocyanide-like Spectrum with Reduced Cytochrome P-450 in Hepatic Microsomes

Franklin, Michael R.

doi:10.3109/00498257109112269

Cited by 134 publications

(27 citation statements)

References 14 publications

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“…1A). The oxidation of this group often leads to the formation of carbene complexes with ferrous heme iron of cytochrome P450 (Franklin, 1971). Since the formation of an MI complex is dependent upon catalytic rate, the susceptibility to MBI is expected to be dependent upon the relative activities of cytochrome P450 variants (Polasek and Miners, 2007;Orr et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Inhibition Kinetics of (S)-Warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy

et al. 2013

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Noscapine is an antitussive and potential anticancer drug. Clinically significant interactions between warfarin and noscapine have been previously reported. In this study, to provide a basis for warfarin dosage adjustment, the inhibition kinetics of noscapine against warfarin metabolism was characterized. Our enzyme kinetics data obtained from human liver microsomes and recombinant CYP2C9 proteins indicate that noscapine is a competitive inhibitor of the (S)-warfarin 7-hydroxylation reaction by CYP2C9. Interestingly, noscapine also inhibited (S)-warfarin metabolism in a NADPHand time-dependent manner, and removal of unbound noscapine and its metabolites by ultrafiltration did not reverse inhibition of (S)-warfarin metabolism by noscapine, suggesting mechanism-based inhibition of CYP2C9 by noscapine. Spectral scanning of the reaction between CYP2C9 and noscapine revealed the formation of an absorption spectrum at 458 nm, indicating the formation of a metabolite-intermediate complex. Surprisingly, noscapine is a 2-to 3-fold more efficient inactivator of CYP2C9.2 and CYP2C9.3 variants than it is of the wild type, by unknown mechanisms. Based on the inhibitory kinetic data, (S)-warfarin exposure is predicted to increase up to 7-fold (depending on CYP2C9 genotypes) upon noscapine coadministration, mainly due to mechanism-based inactivation of CYP2C9 by noscapine. Together, these results indicate that mechanism-based inhibition of CYP2C9 by noscapine may dramatically alter pharmacokinetics of warfarin and provide a basis for warfarin dosage adjustment when noscapine is coadministered.

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Section: Discussionmentioning

confidence: 99%

Characterization of Inhibition Kinetics of (S)-Warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy

et al. 2013

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“…Several, but not all, methylenedioxyaryl-containing compounds have been shown to form metabolite complexes with P450 (Franklin, 1971). Structural requirements appear to include both a methylenedioxyaryl configuration and compound lipophilicity.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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

confidence: 99%

“…Certain methylenedioxyphenyl compounds interact with the mixedfunction oxidases to form metabolite complexes with cytochrome P450 (P450) (Franklin, 1971;Philpot and Hodgson, 1972;Hodgson and Philpot, 1974;Fennell et al, 1980;Murray et al, 1985). 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).…”

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

confidence: 99%

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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

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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“…However, the cytochrome b5 content remained greatly increased (250% of control). The loss of drug-metabolizing enzyme activities, the increase in cytochrome P-450 content and the apparent increase in cytochrome b5 content are attributed to the interaction of safrole with the endoplasmic reticulum, as observed with a number of methylenedioxyphenol compounds (Franklin, 1971;Lake & Parke, 1972).…”

mentioning

confidence: 99%

Structure-activity relationships for the induction and inhibition of hepatic microsomal enzymes in the rat by organohalogen compounds

Franklin¹,

el-Tayeb²

1972

Biochemical Journal

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The Enzymic Formation of a Methylenedioxyphenyl Derivative Exhibiting an Isocyanide-like Spectrum with Reduced Cytochrome P-450 in Hepatic Microsomes

Cited by 134 publications

References 14 publications

Characterization of Inhibition Kinetics of (S)-Warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy

Characterization of Inhibition Kinetics of (S)-Warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy

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

Structure-activity relationships for the induction and inhibition of hepatic microsomal enzymes in the rat by organohalogen compounds

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The Enzymic Formation of a Methylenedioxyphenyl Derivative Exhibiting an Isocyanide-like Spectrum with Reduced Cytochrome P-450 in Hepatic Microsomes

Cited by 134 publications

References 14 publications

Characterization of Inhibition Kinetics of (S)-Warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy

Characterization of Inhibition Kinetics of (S)-Warfarin Hydroxylation by Noscapine: Implications in Warfarin Therapy

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

Structure-activity relationships for the induction and inhibition of hepatic microsomal enzymes in the rat by organohalogen compounds

Contact Info

Product

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About

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