The bronchopulmonary pharmacology of SK&F 104353 in anesthetized guinea pigs: demonstration of potent and selective antagonism of responses to peptidoleukotrienes.
The bronchopulmonary pharmacology of SK&F 104353 [2(S)-hydroxy-3(R)-[2(2-carboxyethyl)thio]-3[2-(8- phenyloctyl)phenyl]-propanoic acid], a potent and selective leukotriene (LT) receptor antagonist in vitro, was assessed in anesthetized, spontaneously breathing guinea pigs. Aerosol administration of SK&F 104353 (5-2000 micrograms/ml x 100 breaths) reduced in a concentration-dependent manner the response to a standard LTD4 challenge (4.33 micrograms/ml x 5 breaths) given 30 min later. Inhalation of a 2000 micrograms/ml solution abolished LTD4-induced bronchoconstriction for at least 2 hr. The i.v. administration of SK&F 104353 10 min before challenge antagonized LTD4-induced bronchoconstriction with an ID50 of 0.55 mumol/kg (0.25 mg/kg). Substantial antagonism of LTD4-induced bronchospasm was observed for at least 60 min after i.v. administration of 5 mumol/kg of SK&F 104353. Infusion of SK&F 104353 at various rates revealed that a steady-state plasma concentration of 0.125 microM (0.06 micrograms/ml) reduced LTD4-induced bronchoconstriction by 60%. In addition to preventing the response to LTD4, i.v. administered SK&F 104353 (10 mumol/kg) rapidly and completely reversed ongoing LTD4-induced bronchoconstriction. SK&F 104353 also was effective when given intraduodenally 1 hr before LTD4 challenge, although the ID50 (32 mumol/kg) was 60-fold greater than the i.v. ID50. Given intragastrically, 100 mumol/kg of SK&F 104353 abolished the response to LTD4 for 1 hr, and reduced the response for 6 hr. SK&F 104353 (20 mumol/kg i.v.) had no effect on the bronchoconstriction induced by aerosolized acetylcholine, histamine or U-44069, but did antagonize the response to LTC4. SK&F 104353 alone did not produce bronchoconstriction when administered by any route or dose.(ABSTRACT TRUNCATED AT 250 WORDS)
Torphy
T J
TJ
Department of Pharmacology, Smith Kline and French Laboratories, King of Prussia, Pennsylvania.
Newton
J F
JF
Wasserman
M A
MA
Vickery-Clark
L
L
Osborn
R R
RR
Bailey
L S
LS
Yodis
L A
LA
Underwood
D C
DC
Hay
D W
DW
D000336:Aerosols; D000758:Anesthesia; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects*; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D006168:Guinea Pigs; D007275:Injections, Intravenous; D008297:Male; D011485:Protein Binding; D011971:Receptors, Immunologic / Q000187:drug effects; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000037:antagonists & inhibitors*
D000336:Aerosols; D001798:Blood Proteins; D003998:Dicarboxylic Acids; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C052393:pobilukast