title: Pharmacologic and pharmacokinetic profile of SK&F S-106203, a potent, orally active peptidoleukotriene receptor antagonist, in guinea-pig.
abstract: In this report the pharmacologic and pharmacokinetic profile of the leukotriene receptor antagonist 3(S)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl] propanoic acid (SK&F S-106203) in guinea-pigs is described. In isolated guinea-pig tracheae SK&F S-106203 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 7.6). SK&F S-106203 was also a potent antagonist of LTE4-induced contractions (pKB = 7.3), but had little effect on those elicited by LTC4 (pKB = 5.5). SK&F S-106203 (10 microM) had no effect on contractions produced by histamine, carbachol, KCl, U-44069, PGF2 alpha or PGD2. In addition, SK&F S-106203 (10 microM) did not inhibit cyclic nucleotide phosphodiesterase (PDE) activity of several PDE isozymes. In guinea-pig lung membrane preparations, SK&F S-106203 was a potent antagonist of 3H-LTD4 binding with a Ki = 19.4 +/- 2.1 nM (n = 5). The pharmacokinetic profile of SK&F S-106203 was determined in unanesthetized guinea-pigs. Following an i.v. (bolus) dose (25 mg/kg), SK&F S-106203 disappeared from plasma in a biphasic fashion with half-lives of 0.1 h (50% of the area under the plasma concentration-time curve, AUC) and 11 h. The AUC obtained for SK&F S-106203 following i.v. administration was 87.3 +/- 7.5 micrograms-h/ml. Following an oral dose of SK&F S-106203 (100 mg/kg), the maximal plasma concentration (Cmax) and the time Cmax was achieved (Tmax) were 21.62 +/- 2.26 micrograms/ml and 4 +/- 1 h, respectively; the AUC was 279.9 +/- 41.8 micrograms-h/ml. Studies examining the effects of i.v. infusion of SK&F S-106203 revealed that marked inhibition of LTD4-induced bronchospasm was produced with steady-state plasma levels of SK&F S-106203 less than 1 microgram/ml (less than 2 microM). Oral (p.o.) pretreatment with 100 mumol/kg SK&F S-106203 for up to 24 h essentially abolished LTD4-induced bronchospasm; this correlated with sustained plasma concentrations of greater than 2 micrograms/ml. The results indicate that in guinea-pig airways, SK&F S-106203 is a potent and selective LT receptor antagonist that is active via aerosol, oral and i.v. routes of administration. When given orally, SK&F S-106203 is highly bioavailable and has a very long duration of action which correlates with the pharmacokinetic profile of the compound. SK&F S-106203 may be useful therapy in asthma and other disorders in which the LTs are thought to play a prominent pathophysiological role.
authors.affiliation: Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
authors.forename: D W
authors.initials: DW
authors.lastname: Hay
authors.forename: R M
authors.initials: RM
authors.lastname: Muccitelli
authors.forename: L M
authors.initials: LM
authors.lastname: Vickery-Clark
authors.forename: L S
authors.initials: LS
authors.lastname: Novak
authors.forename: R R
authors.initials: RR
authors.lastname: Osborn
authors.forename: J G
authors.initials: JG
authors.lastname: Gleason
authors.forename: L A
authors.initials: LA
authors.lastname: Yodis
authors.forename: C M
authors.initials: CM
authors.lastname: Saverino
authors.forename: R D
authors.initials: RD
authors.lastname: Eckardt
authors.forename: H M
authors.initials: HM
authors.lastname: Sarau
mesh_terms: D000818:Animals; D003998:Dicarboxylic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
chemical_list: D003998:Dicarboxylic Acids; D010726:Phosphodiesterase Inhibitors; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; C065234:SK&F S-106203; C052393:pobilukast