Oral pharmacokinetics and <i>in-vitro</i> metabolism of metyrapone in male rats

Murata, Hideyuki; Higuchi, Toshiyuki; Otagiri, Masaki

doi:10.1111/jphp.12560

Cited by 4 publications

(16 citation statements)

References 25 publications

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“…MP which contains a ketone group is reduced to a secondary alcohol metabolite, metyrapol (MPOL) (Figure 1). Our recent study [11] demonstrated that, after a single oral administration of MP to male Wistar rats, MPOL was the major metabolite and its concentration was maintained at levels higher than these for MP in plasma. The major site involved in the reduction to MPOL in the rats is the liver, and the high MP reducing activity is presented in the liver microsomal fraction [11].…”

Section: Introductionmentioning

confidence: 93%

“…Our recent study [11] demonstrated that, after a single oral administration of MP to male Wistar rats, MPOL was the major metabolite and its concentration was maintained at levels higher than these for MP in plasma. The major site involved in the reduction to MPOL in the rats is the liver, and the high MP reducing activity is presented in the liver microsomal fraction [11]. Additionally, we previously reported that the rat liver MP-reducing enzyme is present in not only the microsomal fraction but also the mitochondrial fraction [11].…”

Section: Introductionmentioning

confidence: 93%

“…Five metabolites of MP, MPOL, the form in which either of two pyridyl nitrogen atoms, MP N-oxide I (MP NOI) and MP N-oxide II (MP NOII), and the form in which the ketone group is reduced, MPOL N-oxide I (MPOL NOI) and MPOL N-oxide II (MPOL NOII) ( Figure 1) were synthesized according to our previous report [11]. NADP + , glucose-6-phosphate (G-6-P) and glucose-6-phosphate dehydrogenase (G-6-PDH) were purchased from Oriental Yeast Co., Ltd. (Tokyo, Japan).…”

Section: Chemicalsmentioning

confidence: 99%

“…The major site involved in the reduction to MPOL in the rats is the liver, and the high MP reducing activity is presented in the liver microsomal fraction [11]. Additionally, we previously reported that the rat liver MP-reducing enzyme is present in not only the microsomal fraction but also the mitochondrial fraction [11]. Since many drug-metabolizing enzymes including reductase activity for ketone-containing drugs are present in the mitochondrial fraction [12], we hypothesized that the rat mitochondrial fraction plays a role in the reduction of MP in addition to the microsomal fraction.…”

Section: Introductionmentioning

confidence: 99%

“…Since many drug-metabolizing enzymes including reductase activity for ketone-containing drugs are present in the mitochondrial fraction [12], we hypothesized that the rat mitochondrial fraction plays a role in the reduction of MP in addition to the microsomal fraction. Furthermore, we proposed that the major enzyme involved in reduction of MP to MPOL is 11β-HSD1 in both subcellular fractions similar to the human liver [11]. Therefore, it is conceivable that the The metabolizing enzyme activity of a drug is often modulated by the co-administration of inhibitors or inducers that affect the drug-metabolizing enzyme.…”

Section: Introductionmentioning

confidence: 99%

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Invitro and Invivo Inhibition of Metyraponemetabolism by Glycyrrhetinic Acid in Male Wistar Rats

2016

J Pharm Pharmacol

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Objectives: We investigated the inhibitory effect of glycyrrhetinic acid (GA), an 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor, on the reductive metabolism of metyrapone (MP) in an invitro study, and the effect of the co-administration of GA on the pharmacokinetics of MP and its metabolites in rats.Methods: High-performance liquid chromatography was used to determine the metabolic activities of MP in the liver and testis and the plasma concentrations of MP and its metabolites after MP with or without a GA dose to rats.Results: GA strongly inhibited the reduction of MP to metyrapol (MPOL) in the microsomal and mitochondrial fractions of both the tissues in a dose-dependent manner. When GA was co-administrated, the plasma levels of MPOL and MPOL N-oxide II (MPOL NOII) were lower than those of MP alone, while the levels of MP and MP NOII were higher than those of MP alone. Conclusion:The invitro GA inhibition suggests that the reduction of MP in the rat liver and testis is catalyzed by 11β-HSD1. The coadministration of GA modulated the plasma pharmacokinetics of MP, MPOL, MP NOII and MPOL NOII, suggesting that the changes in the pharmacokinetics were caused by the inhibition of 11β-HSD1 invivo.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 93%

Section: Chemicalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Invitro and Invivo Inhibition of Metyraponemetabolism by Glycyrrhetinic Acid in Male Wistar Rats

2016

J Pharm Pharmacol

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Molecular Determinants of Substrate Affinity and Enzyme Activity of a Cytochrome P450BM3 Variant

Geronimo

Denning

Heidary

et al. 2018

Biophysical Journal

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Cytochrome P450 catalyzes the hydroxylation and/or epoxidation of fatty acids, fatty amides, and alcohols. Protein engineering has produced P450 variants capable of accepting drug molecules normally metabolized by human P450 enzymes. The enhanced substrate promiscuity has been attributed to the greater flexibility of the lid of the substrate channel. However, it is not well understood how structurally different and highly polar drug molecules can stably bind in the active site nor how the activity and coupling efficiency of the enzyme may be affected by the lack of enzyme-substrate complementarity. To address these important aspects of non-native small molecule binding, this study investigated the binding of drug molecules with different size, charge, polar surface area, and human P450 affinity on the promiscuous R47L/F87V/L188Q/E267V/F81I pentuple mutant of P450. Binding free energy data and energy decomposition analysis showed that pentuple mutant P450 stably binds (i.e., negative ΔG°) a broad range of substrate and inhibitor types because dispersion interactions with active site residues overcome unfavorable repulsive and electrostatic effects. Molecular dynamics simulations revealed that 1) acidic substrates tend to disrupt the heme propionate A-K69 salt bridge, which may reduce heme oxidizing ability, and 2) the lack of complementarity leads to high substrate mobility and water density in the active site, which may lead to uncoupling. These factors must be considered in future developments of P450 as a biocatalyst in the large-scale production of drug metabolites.

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Optimal timing of oral metyrapone intake for the suppression of cold-pressor stress-induced cortisol release

Drost

Finke

Behrje

et al. 2023

Psychoneuroendocrinology

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Oral pharmacokinetics and in-vitro metabolism of metyrapone in male rats

Abstract: In this study, we elucidated the plasma pharmacokinetics of MP and its metabolites in male rats after an oral administration. MPOL is most likely to be produced by 11β-HSD1 in the male rats and humans.

Cited by 4 publications

References 25 publications

Invitro and Invivo Inhibition of Metyraponemetabolism by Glycyrrhetinic Acid in Male Wistar Rats

Invitro and Invivo Inhibition of Metyraponemetabolism by Glycyrrhetinic Acid in Male Wistar Rats

Molecular Determinants of Substrate Affinity and Enzyme Activity of a Cytochrome P450BM3 Variant

Optimal timing of oral metyrapone intake for the suppression of cold-pressor stress-induced cortisol release

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