Proadifen‐sensitive High Affinity Binding of3H‐Alaproclate to Liver Membranes

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Abstract
3H‐Alaproclate, a selective 5‐hydroxytryptamine uptake inhibitor, was found to bind to microsomal membranes from the rat liver with high affinity (KD= 3 nM) and large capacity (Bmaxabout 2 nmol/g liver). This binding was stereoselective since S‐(‐)‐alaproclate was 30 times more potent than the R‐(+)‐enantiomer to displace the3H‐labelled racemate. Proadifen (SKF 525A), an inhibitor of cytochrome P‐450, displaced the3H‐alaproclate binding with the same, high affinity (Ki= 3 nM) as alaproclate itself. Repeated treatment with phenobarbital sodium (5 × 75 mg/kg intraperitoneally) increased the number of alaproclate binding sites 7–8 times without changing the affinity. However, most of the phenobarbital induced3H‐alaproclate binding was not displaceable by proadifen, showing the presence of at least two different high affinity binding sites. The possible involvement of cytochrome P‐450 in the alaproclate binding is discussed.