Carbapenem antibiotics reduce valproic acid (VPA) concentrations quickly and dramatically
Why does this happen?
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Why does this happen?
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The carbapenem-VPA interaction was first described in 1997
Here, an 8-year-old girl with a seizure disorder and pneumonia is treated with panipenem
Thereafter, her [VPA] falls from 30.1 µg/mL (209 µM) to 1.53 µg/mL (11 µM)
academic.oup.com/jac/article/39…
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Here, an 8-year-old girl with a seizure disorder and pneumonia is treated with panipenem
Thereafter, her [VPA] falls from 30.1 µg/mL (209 µM) to 1.53 µg/mL (11 µM)
academic.oup.com/jac/article/39…
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There are many similar reports, all with the same theme:
A rapid, dramatic drop in [VPA], often accompanied by a loss of seizure control
journals.lww.com/drug-monitorin…
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A rapid, dramatic drop in [VPA], often accompanied by a loss of seizure control
journals.lww.com/drug-monitorin…
/3
By far the largest series (n=381) comes from a single neurosurgical unit in China
Left: [VPA] by dose (1.2 or 1.6 g/day) in patients receiving/not receiving meropenem
Right: gradual resolution after mero is stopped
onlinelibrary.wiley.com/doi/abs/10.111…
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Left: [VPA] by dose (1.2 or 1.6 g/day) in patients receiving/not receiving meropenem
Right: gradual resolution after mero is stopped
onlinelibrary.wiley.com/doi/abs/10.111…
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Why this happens relates to how VPA is metabolized
The metabolic fate of VPA is usually described like this, with glucuronidation playing an important role
europepmc.org/article/pmc/pm…
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The metabolic fate of VPA is usually described like this, with glucuronidation playing an important role
europepmc.org/article/pmc/pm…
/5
What’s almost never mentioned is that VPA-glucuronide is metabolized *back* to VPA
This is done by an enzyme called acylpeptide hydrolase (APEH)
APEH just removes the glucuronide moiety (blue), leaving us with good old VPA
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This is done by an enzyme called acylpeptide hydrolase (APEH)
APEH just removes the glucuronide moiety (blue), leaving us with good old VPA
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This puzzling interaction was explained in 2010 by scientists in Japan, who purified what was then called “VPA-glucuronide hydrolase” from human liver
First they identified it as APEH
Then they showed it was inhibited by panipenem
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First they identified it as APEH
Then they showed it was inhibited by panipenem
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In a way, APEH is just another enzyme inhibited by carbapenems. This is how they work.
They acylate penicillin binding proteins (PBPs)—transpeptidases, carboxypeptidases, etc.—involved in the synthesis of peptidoglycan, the major component of bacterial cell walls.
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They acylate penicillin binding proteins (PBPs)—transpeptidases, carboxypeptidases, etc.—involved in the synthesis of peptidoglycan, the major component of bacterial cell walls.
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Worth noting that all carbapenems lower [VPA], although imipenem might do so to a lesser extent
And the interaction isn’t easily overcome by a higher dose of VPA
journals.lww.com/drug-monitorin…
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And the interaction isn’t easily overcome by a higher dose of VPA
journals.lww.com/drug-monitorin…
/9
In an interesting twist, the interaction has been exploited to treat deliberate VPA overdose
In this report, erta and then mero were given to an intubated patient who'd taken ~26 g of VPA
sciencedirect.com/science/articl…
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In this report, erta and then mero were given to an intubated patient who'd taken ~26 g of VPA
sciencedirect.com/science/articl…
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To sum up:
1. Carbapenems lower [VPA] by inhibiting conversion of VPA-G to VPA
2. This happens quickly and is not easily overcome by more VPA
3. The interaction resolves gradually after the carbapenem is stopped
4. Carbapenems might have a role in severe VPA overdose
/ end
1. Carbapenems lower [VPA] by inhibiting conversion of VPA-G to VPA
2. This happens quickly and is not easily overcome by more VPA
3. The interaction resolves gradually after the carbapenem is stopped
4. Carbapenems might have a role in severe VPA overdose
/ end
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