<i>In vitro</i> evaluation of valproic acid as an inhibitor of human cytochrome P450 isoforms: preferential inhibition of cytochrome P450 2C9 (CYP2C9)

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<jats:p><jats:bold>Aims </jats:bold> To evaluate the potency and specificity of valproic acid as an inhibitor of the activity of different human CYP isoforms in liver microsomes.</jats:p><jats:p><jats:bold>Methods </jats:bold> Using pooled human liver microsomes, the effects of valproic acid on seven CYP isoform specific marker reactions were measured: phenacetin <jats:italic>O</jats:italic>‐deethylase (CYP1A2), coumarin 7‐hydroxylase (CYP2A6), tolbutamide hydroxylase (CYP2C9), <jats:italic>S</jats:italic>‐mephenytoin 4′‐hydroxylase (CYP2C19), dextromethorphan <jats:italic>O</jats:italic>‐demethylase (CYP2D6), chlorzoxazone 6‐hydroxylase (CYP2E1) and midazolam 1′‐hydroxylase (CYP3A4).</jats:p><jats:p> <jats:bold> <jats:italic>Results </jats:italic> </jats:bold>Valproic acid competitively inhibited CYP2C9 activity with a <jats:italic>K</jats:italic><jats:sub>i</jats:sub> value of 600 µ<jats:sc>m</jats:sc>. In addition, valproic acid slightly inhibited CYP2C19 activity (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> = 8553 µ<jats:sc>m</jats:sc>, mixed inhibition) and CYP3A4 activity (<jats:italic>K</jats:italic><jats:sub>i</jats:sub> = 7975 µ<jats:sc>m</jats:sc>, competitive inhibition). The inhibition of CYP2A6 activity by valproic acid was time‐, concentration‐ and NADPH‐dependent (<jats:italic>K</jats:italic><jats:sub>I</jats:sub> = 9150 µ<jats:sc>m</jats:sc>, <jats:italic>K</jats:italic><jats:sub>inact</jats:sub>=0.048 min<jats:sup>−1</jats:sup>), consistent with mechanism‐based inhibition of CYP2A6. However, minimal inhibition of CYP1A2, CYP2D6 and CYP2E1 activities was observed.</jats:p><jats:p> <jats:bold> <jats:italic>Conclusions </jats:italic> </jats:bold>Valproic acid inhibits the activity of CYP2C9 at clinically relevant concentrations in human liver microsomes. Inhibition of CYP2C9 can explain some of the effects of valproic acid on the pharmacokinetics of other drugs, such as phenytoin. Co‐administration of high doses of valproic acid with drugs that are primarily metabolized by CYP2C9 may result in significant drug interactions.</jats:p>

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