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)-1(2-carboxyethyl)thio]-3-12-(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) D 4-induced contractions (pA 2 = 7.6). SK&F S-106203 was also a potent antagonist of LTE 4-induced contractions (pK B = 7.3), but had little effect on those elicited by LTC 4 (pK B = 5.5). SK&F S-106203 (10 μM) had no effect on contractions produced by histamine, carbachol, KCI, U-44069, PGF 2α or PGD 2. In addition, SK&F S-106203 (10 μM) 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-LTD 4 binding with a K i = 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 μg-h/ml. Following an oral dose of SK&F S-106203 (100 mg/kg), the maximal plasma concentration (C max) and the time C max was achieved (T max were 21.62 ± 2.26 kg/ml and 4 ± 1 h, respectively; the AUC was 279.9 ± 41.8 μg-h/ml. Studies examining the effects of i.v. infusion of SK&F S-106203 revealed that marked inhibition of LTD 4-induced bronchospasm was produced with steady-state plasma levels of SK&F S-106203 < 1 μg/ml (< 2 μM). Oral (p.o.) pretreatment with 100 μmol/kg SK&F S-106203 for up to 24 h essentially abolished LTD 4-induced bronchospasm; this correlated with sustained plasma concentrations of > 2 μg/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 Us are thought to play a prominent pathophysiological role.