Effect of the leukotriene receptor antagonists FPL 55712, LY 163443, and MK-571 on the elimination of cysteinyl leukotrienes in the rat.
1. Leukotriene elimination via bile and urine is an important mechanism of inactivation for these potent lipid mediators. We investigated whether the elimination of cysteinyl leukotrienes is a target for the action of leukotriene receptor antagonists. 2. Experiments were performed in male rats under deep thiopentone anaesthesia. The bile duct and the urinary bladder were cannulated. Tritium labelled leukotrienes and leukotriene receptor antagonists were given via central venous catheters. Elimination of leukotrienes produced in vivo was studied following stimulation of endogenous leukotriene biosynthesis by operative trauma. 3H-leukotriene metabolites were identified by h.p.l.c. analysis. Leukotrienes produced in vivo were measured by combined use of h.p.l.c. and RIA. 3. Under control conditions, 49 +/- 12% of the injected 3H-leukotriene radioactivity was recovered in bile and 1 +/- 0.8% in urine within 90 min. Operative trauma resulted in initial hepatobiliary secretion of 887 +/- 206 pmol kg-1 h-1 of the endogenous leukotriene metabolite N-acetyl leukotriene E4 (LTE4NAc). 4. FPL 55712 strongly inhibited hepatobiliary elimination of 3H-leukotriene radioactivity in a dose-dependent manner after i.v. injection of [3H]-LTC4, [3H]-LTD4 or [3H]LTE4, respectively. Biliary [3H]-LTD4 was reduced most effectively. The leukotriene antagonist potently prevented biliary elimination of LTE4NAc produced in vivo. Bile flow and elimination from blood into bile of [3H]-ouabain were also impaired by FPL 55712, but to a lesser extent. 5. LY 163443 reduced biliary [3H]-LTD4 after i.v. administration of [3H]-LTD4. However, the total elimination of 3H-leukotriene metabolites into bile was not significantly inhibited by the drug. 6. MK-571 reduced the biliary concentration of tracer after administration of 3H-leukotrienes most potently with respect to [3H]-LTD4. In contrast, the total recovery of 3H-leukotrienes in bile tended to increase. This is explained by a drug-induced increase in bile flow. 7. Urinary elimination of 3H-leukotrienes, quantitatively less important in the rat, was not significantly influenced by the leukotriene receptor antagonists. Recovery of 3H-leukotriene radioactivity in liver and kidneys was quantitatively insignificant. 8. From our data, we conclude that leukotriene receptor antagonists have the potential to affect leukotriene elimination by a mechanism not necessarily related to receptor blockade. Inhibition of elimination by the receptor antagonists may prolong the biological half life of leukotrienes. This effect may counteract the antagonistic properties of these drugs.
Denzlinger
C
C
Klinikum Grosshadern, Ludwig-Maximilians Universität, München, West Germany.
Grimberg
M
M
Kapp
A
A
Haberl
C
C
Wilmanns
W
W
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D001646:Bile / Q000187:drug effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D002867:Chromones / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis / Q000378:metabolism* / Q000652:urine; D008297:Male; D011422:Propionates / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D011919:Rats, Inbred Strains; D013189:SRS-A / Q000037:antagonists & inhibitors*
D000098:Acetophenones; D002867:Chromones; D015289:Leukotrienes; D011422:Propionates; D011804:Quinolines; D013189:SRS-A; C059141:verlukast; C006312:FPL 55712; C049043:LY 163443