Metabolic disposition of leukotriene B4 (LTB4) and oxidation-resistant analogues of LTB4 in conscious rabbits.
1. The kinetics of leukotriene B4 (LTB4), after single i.v. injections of doses of 0.1 to 1 micrograms kg-1, were investigated in conscious rabbits and compared with those of the omega- and beta-oxidation resistant bioactive analogues, 20, 20, 20-trifluoro-LTB4 (20-F3-LTB4) and 3-thio-LTB4, respectively. 2. Immunoreactive LTB4 (IR-LTB4) elimination was first-order, as shown by a constant systemic clearance (ClLTB4) 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-LTB4 after continuous infusion of LTB4 and those predicted by using the mean estimated ClLTB4 of 93 +/- 4 ml min-1 kg-1, further confirming the linearity of IR-LTB4 elimination. 3. The half-life (t1/2) or IR-LTB4 increased from 0.47 +/- 0.02 to 0.63 +/- 0.04 min as a consequence of a change in the apparent volume of distribution (Vd) from 72 +/- 5 to 109 +/- 13 ml kg-1, for the 0.1 and 1 micrograms kg-1 doses injected, respectively. 4. Single i.v. injections of [3H]-LTB4 (4.7 ng kg-1) were administered, and the decay of plasma [3H]-LTB4 following h.p.l.c. purification was used to estimate the kinetic parameters. The kinetic parameters of [3H]-LTB4 were characterized by a mean systemic clearance (Cl) of 96 +/- 11 ml min-1 kg-1, a t1/2 of 0.53 +/- 0.03 min, and an apparent Vd of 85 +/- 9 ml kg-1, similar to the parameters obtained after LTB4 boluses. 5. The disposition of LTB4 analogues, whether resistant to Omega- or to Beta-oxidation in vitro, did not differ significantly from the disposition of the LTB4 molecule. The half-lives of 20-F3-LTB4 and 3-thio-LTB4 in the circulation were 0.52 +/- 0.07 min and 0.70 +/- 0.11 min, respectively.6. In summary, our results showed that LTB4, as well as Omega-oxidation- and Beta-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 LTB4.
Marleau
S
S
Centre de recherche en Rhumatologie et Immunologie, Université Laval, Québec, Canada.
Dallaire
N
N
Poubelle
P E
PE
Borgeat
P
P
D000818:Animals; D006207:Half-Life; D007975:Leukotriene B4 / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D008297:Male; D010084:Oxidation-Reduction; D011817:Rabbits; D014018:Tissue Distribution
D007975:Leukotriene B4