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1. The 5-lipoxygenase inhibitor (I), a substituted benzothiazole is metabolized mainly by glucuronide and/or sulphate conjugation in rat, guinea-pig, beagle and rhesus monkey. Glucuronidation is the major pathway, and sulphation is more extensive in rat and beagle than in guinea-pig and rhesus monkey. 2. After a single oral dosing of 14C-I (10 mg/kg), more than 96% of the dose was excreted in 7 days in all four species, however there is species difference in urinary excretion, which was 2.8 +/- 0.3% in rat, 46.9 +/- 1.6% in guinea-pig, 2.6% in beagle and 68.2% in rhesus monkey. 3. After a single i.v. dose of 14C-I to bile duct-cannulated rats and guinea pigs, bile was a major route of elimination, and in rats the ratio of glucuronide to sulphate in excreta increased from 0.71 +/- 0.01 to 0.93 +/- 0.05 as the dose was increased from 0.2 to 20 mg/kg.

Fundamental studies were conducted to examine the release of histamine and leukotriene (LT) C₄ from lung fragments of guinea pigs and the effects of E6080 on the release of LTB₄ and LTC₄ from lung fragments or inflammatory cells. The release of histamine and LTs showed large interindividual variations and a marked dependence on experimental conditions. Addition of 10 mML-cysteine significantly increased LTC₄ release compared with that in its absence (about 1.7 times, in terms of mean value). E6080 inhibited antigen-stimulated LTB₄ and LTQ release from passively sensitized human (IC₅₀: LTB₄ 0.08 µM, LTC₄ 0.2 µM) and guinea-pig lung fragments (IC₅₀: LTQ 1.1 µM). The LTB₄ and LTQ releases from healthy human polymorphonuclear leukocytes (calcium ionophore A23187) and from allergic patients’ leukocytes (basophils, antigen) were inhibited by E6080 with IC₅₀ values of below 1.0 µM Furthermore, the LTQ release from rat alveolar macrophages (silica particles) was inhibited by E6080 with an IC₅₀ of 0.2 µM The potent inhibition by E6080 might be a result of the inhibition of 5-lipoxygenase, since 5-lipoxygenase in rat basophilic leukemia cell was inhibited by E6080 with an IC₅₀ of 0.2 µM The results confirm the potent inhibitory effects of E6080 on the release of LTs.