Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on bronchial anaphylaxis in anaesthetized guinea‐pigs

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Abstract
The effect of a novel series of orally‐active acetohydroxamic acid inhibitors of arachidonate 5‐lipoxygenase on ‘leukotriene‐dependent’ anaphylactic bronchoconstriction has been investigated in anaesthetized, pump‐ventilated guinea‐pigs actively sensitized to ovalbumin (OA). In a complementary series of experiments, the pharmacokinetics of these compounds in the plasma compartment following oral administration to guinea‐pigs has also been investigated. In animals pretreated with mepyramine (2 mg kg−1 i.v.) and indomethacin (l0 mg kg−1 i.v.) and challenged with antigen aerosol (OA 10 mg ml−1; 5s) compounds BW A4C, BW A137C and BW A797C (10–200 mg kg−1, p.o., 1 h pre‐challenge) markedly reduced that component of anaphylactic bronchoconstriction shown to be ‘leukotriene‐dependent’. The maximum degree of inhibition (up to 75%) of ‘leukotriene‐dependent’ anaphylactic bronchoconstriction by these three compounds was equivalent to that seen with the leukotriene antagonist FPL 55712 (10 mg kg−1, i.v.). The peak levels of unchanged acetohydroxamic adds in the plasma compartment occurred 0.5 h after their oral administration and were as follows: BW A4C: 11.3 ± 3.9; BW A137C: 7.6 ± 2.4; BW A797C: 3.9 ± 1.3 μg ml−1 plasma. The inhibition by BW A4C and BW A137C (50 mg kg−1, p.o.) of ‘leukotriene‐dependent’ anaphylactic bronchospasm persisted for up to 3 and 4h respectively but did not extend to 6h. The decline in inhibitory activity paralleled the fall in the concentration of unchanged drug in the plasma compartment over this time period. The results of the present study are consistent with BW A4C, BW A137C and BW A797C attenuating ‘leukotriene‐dependent’ bronchial anaphylaxis in anaesthetized guinea‐pigs by selective inhibition of arachidonate 5‐lipoxygenase.