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Metabolic disposition of leukotriene B 4 (LTB4) and oxidation‐resistant analogues of LTB4 in conscious rabbits
Author(s) -
Marleau Sylvie,
Dallaire Nancy,
Poubelle Patrice E.,
Borgeat Pierre
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb13125.x
Subject(s) - leukotriene b4 , chemistry , leukotriene , steady state (chemistry) , kinetics , medicine , inflammation , asthma , physics , quantum mechanics
1 The kinetics of leukotriene B 4 (LTB 4 ), after single i.v. injections of doses of 0.1 to 1 μg kg −1 , were investigated in conscious rabbits and compared with those of the Ω‐ and β‐oxidation resistant bioactive analogues, 20, 20, 20‐trifluoro‐LTB 4 (20‐F 3 ‐LTB 4 ) and 3‐thio‐LTB 4 , respectively. 2 Immunoreactive LTB 4 (IR‐LTB 4 ) elimination was first‐order, as shown by a constant systemic clearance (Cl LTB4 ) and a proportional increase in the area under the curve (AUC) of the plasma concentration versus time curve over the dose‐range studied. Our results showed a good correlation between observed steady‐state plasma concentrations (Css) of IR‐LTB 4 after continuous infusion of LTB 4 and those predicted by using the mean estimated Cl LTB4 of 93 ± 4 ml min −1 kg −1 , further confirming the linearity of IR‐LTB 4 elimination. 3 The half‐life ( t ½ ) or IR‐LTB 4 increased from 0.47 ± 0.02 to 0.63 ± 0.04 min as a consequence of a change in the apparent volume of distribution ( V d ) from 72 ± 5 to 109 ± 13 ml kg −1 , for the 0.1 and 1 μg kg −1 doses injected, respectively. 4 Single i.v. injections of [ 3 H]‐LTB 4 (4.7 ng kg −1 ) were administered, and the decay of plasma [ 3 H]‐LTB 4 following h.p.l.c. purification was used to estimate the kinetic parameters. The kinetic parameters of [ 3 H]‐LTB 4 were characterized by a mean systemic clearance (Cl) of 96 ± 11 ml min −1 kg −1 , a t ½ of 0.53 ± 0.03 min, and an apparent V d of 85 ± 9 ml kg −1 , similar to the parameters obtained after LTB 4 boluses. 5 The disposition of LTB 4 analogues, whether resistant to β‐ or to β‐oxidation in vitro , did not differ significantly from the disposition of the LTB 4 molecule. The half‐lives of 20‐F 3 ‐LTB 4 and 3‐thio‐LTB 4 in the circulation were 0.52 ± 0.07 min and 0.70 ± 0.11 min, respectively. 6 In summary, our results showed that LTB 4 , as well as Ω‐oxidation‐ and β‐oxidation‐resistant analogues were cleared very rapidly from the rabbit circulation and indicate that in situ , metabolism in blood is not a rate‐limiting factor for the elimination of LTB 4 .