Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Tagari, Philip; Ethier, Diane; Ford‐Hutchinson, A. W.; Cirino, Maria

doi:10.1002/bmc.1130040107

Cited by 3 publications

(1 citation statement)

References 15 publications

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“…Similarly, arterial plasma concentrations of LTCa and LTD4 (but not LTE4) have been assessed in guinea-pigs after antiIgE challenges [31]. Leukotriene metabolites have also been measured in bile from monkeys [5], pigs [32], guinea-pigs [33] and rats [34], and in lymph from sheep [35]. However, alI the above methodologies allow the artefactual generation of lipoxygenase products eg.…”

Section: Introductionmentioning

confidence: 99%

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Tagari¹,

Brideau²,

Chan³

et al. 1993

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In man, the therapeutic effectiveness of specific inhibitors of leukotriene (LT) biosynthesis against allergen-induced bronchoconstriction appears to be related to the in vivo biochemical efficacy of these compounds, as measured by inhibition of whole blood LTB4 generation (upon A23187 stimulus) and, particularly, urinary LTE4 excretion. Accordingly, we have assessed the ability of two clinically documented LT biosynthesis inhibitors, zileuton and MK-886, and the structurally novel 5-lipoxygenase activating protein antagonist, MK-0591, to inhibit the production of these inflammatory arachidonic acid metabolites in laboratory dogs. Zileuton (2 mg/kg) was extremely bioavailable in dogs (> 10 microM plasma concentrations), and inhibited the A23187-induced ex vivo production of LTB4 by venous blood by > 90%, in concordance with its potency in canine blood in vitro (IC50 = 1.1 microM). Despite this degree of inhibition in whole blood, urinary LTE4 excretion was reduced by only 52%, a profile of activity similar to that seen in clinical studies. MK-886 was less well absorbed, with plasma concentrations of 3 microM being achieved only at 25 mg/kg. These levels resulted in < 45% inhibition of LTB4 production, but a significant (p < 0.05) 47% inhibition of urinary LTE4 excretion. MK-0591 was similarly bioavailable (compared with MK-886), but 10-fold more active in vivo as a 2 mg/kg dose resulted in 41-62% inhibition of urinary LTE4 excretion (p < 0.05 vs controls; n = 4, 28). Significant inhibition of ex vivo LTB4 synthesis was also observed at this dose (49%), in accord with peak plasma concentrations of 0.5 microM and an in vitro potency of 0.2-0.4 microM (IC50) in whole blood from these animals. At higher dose (10 mg/kg), MK-0591 inhibited LTE4 excretion by 69%, with 88% inhibition of the LT biosynthetic capacity of whole blood. These data demonstrate that the biochemical efficacy of structurally diverse leukotriene biosynthesis inhibitors can be assessed in vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful for predicting biochemical activity in man.

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Section: Introductionmentioning

confidence: 99%

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Tagari¹,

Brideau²,

Chan³

et al. 1993

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Mediators and vascular effects in response toendotoxin

Olson

Hellyer

Dodam

1995

British Veterinary Journal

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Elevated cysteinyl leukotriene excretion in experimental glomerulonephritis

Petric¹,

Ford‐Hutchinson²

1994

Kidney International

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The involvement of cysteinyl leukotrienes (LT) in the etiology of glomerulonephritis (GN) was investigated in a rat model of nephrotoxic serum nephritis in which renal function, morphology, LTC4 synthase activity and urinary cysteinyl LT excretion were monitored over seven days. Significant alterations in renal function and morphology were evident on day 1 in nephritic rats, with a 12% decline in creatinine clearance, a greater than three-fold increase in urinary protein excretion and histologic evidence of basement membrane thickening. Urinary LTC4 excretion in the nephritic rats was elevated at this time to 140 +/- 38 pg/hr (P < 0.01) compared to undetectable levels in control animals. On days 3 and 7, while proteinuria intensified and glomerular filtration remained depressed, LTC4 excretion declined 14% (NS) and 79% (P < 0.05), respectively. The temporal changes in urinary LTC4 excretion were paralleled by concomitant alterations in LTC4 synthase activity in renal cortical microsomes, where an 84% (P < 0.01) drop in enzyme activity occurred from day 1 to day 7 in the nephritic group. This data provides the first measurement of urinary cysteinyl LT excretion and altered LTC4 synthase activity in a model of experimental GN and supports an early role for LT's in the development of subsequent functional changes.

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Application of reversed phase high performance liquid chromatography to the analysis of sulphidopeptide leukotrienes in pig bile

Cited by 3 publications

References 15 publications

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Assessment of thein vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors

Mediators and vascular effects in response toendotoxin

Elevated cysteinyl leukotriene excretion in experimental glomerulonephritis

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