1. 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. 2. In animals pretreated with
mepyramine (2 mg kg-1, i.v.) and
indomethacin (10 mg kg-1, i.v.) and challenged with
antigen aerosol (OA 10 mg ml-1; 5 s) 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'. 3. 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.). 4. The peak levels of unchanged acetohydroxamic
acids 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 micrograms ml-1 plasma. 5. 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 4 h respectively but did not extend to 6 h. The decline in inhibitory activity paralleled the fall in the concentration of unchanged
drug in the plasma compartment over this time period. 6. 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.