What question did this study set out to answer?

To examine the metabolic interaction and evaluate whether phenytoin and tolbutamide share the same cytochrome P450 catalytic pathway in human liver microsomes.

February 1, 1991British Journal of Clinical PharmacologyOpen Access

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

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Authors

CDC. J. DoeckeRoyal Adelaide Hospital MVME VeroneseFlinders Medical Centre SPS. M. PondThe University of Queensland

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Implication

In vitro study demonstrates mutual competitive inhibition between phenytoin and tolbutamide in human liver microsomes, suggesting a shared cytochrome P450 enzyme catalyzes both reactions.

Key Points

To examine the metabolic interaction and evaluate whether phenytoin and tolbutamide share the same cytochrome P450 catalytic pathway in human liver microsomes.
Measured enzyme kinetics and mutual competitive inhibition for phenytoin 4-hydroxylation and tolbutamide methylhydroxylation in human liver microsomes (n = 3).
Correlated hydroxylation rates across microsomes from 18 human livers.
Tested selective chemical inhibitors (sulphaphenazole, mephenytoin) and anti-rabbit P450IIC3 IgG immunoinhibition on both metabolic reactions.
Phenytoin 4-hydroxylation (mean Km = 29.6 µM) was competitively inhibited by tolbutamide (mean Ki = 106.2 µM), while tolbutamide methylhydroxylation (mean Km = 85.6 µM) was competitively inhibited by phenytoin (mean Ki = 22.6 µM).
Hydroxylation activities correlated strongly across 18 human liver microsomal samples (rs = 0.82, P < 0.001).
Both reactions were potently inhibited by sulphaphenazole (IC50 = 0.4 µM for phenytoin, 0.6 µM for tolbutamide) and anti-rabbit P450IIC3 IgG (62% and 68% inhibition, respectively), but poorly inhibited by mephenytoin (IC50 > 400 µM).

Cite This Study

Doecke et al. (1991) studied this question.

synapsesocial.com/papers/6a735bd56cf7a6ca1f6c2f9b https://doi.org/10.1111/j.1365-2125.1991.tb05499.x

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Implication

In vitro study demonstrates mutual competitive inhibition between phenytoin and tolbutamide in human liver microsomes, suggesting a shared cytochrome P450 enzyme catalyzes both reactions.

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

Discussion

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Implication

Key Points

Cite This Study

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

Discussion

Member takes

Implication

Key Points

Cite This Study

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