Species difference of (2R,4R)-2-(o-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thiazolidinec arb oxylic acid (SA446) in inhibition of angiotensin converting enzyme.

A marked species difference was observed both in vitro and in vivo in the activity of SA446, an orally active inhibitor of angiotensin converting enzyme (ACE), as compared with that of captopril in five different animal species. The activity of SA446 in vitro in inhibiting plasma ACE correlated with the activity in vivo as determined by inhibition of the pressor response to angiotensin I (AI). SA446 was more potent as an inhibitor of AI response in dogs, cats and rabbits than in guinea pigs and rats. Furthermore, ACE activity in whole blood in vivo was inhibited by SA446, and the activity of SA446 was also more potent in dogs than in rats. The concentration of SA446 in the ultrafiltrate of blood (free form) was significantly higher in dogs than in rats, while no difference was observed in level of SA446 in the whole blood (free and protein-bound form) between these two species after intravenous injection. The binding rate of SA446 to plasma protein of rats in vitro was more than twice as high as that of dogs. These results suggest that the difference in the protein binding rate of SA446 is reflected in ultrafiltrate level and is one of the important components in defining the species difference in SA446 action.

Renal excretion of an angiotensin I converting enzyme inhibitor (SA-446) in dogs.

The renal excretory mechanism of an orally active inhibitor of angiotensin converting enzyme (SA-446) was examined in anesthetized dogs. Parenteral administration of this compound resulted in production of constant levels of about 2 mg/l in the plasma (PSA) and the urine concentration was 726 +/- 200 mg/l, a level significantly higher than that in the plasma. Renal clearance of SA-446 (CSA) was 2.24 +/- 0.34 ml/g X min and was significantly higher than GFR. The clearance ratio (CSA/GFR) of over 1.0 was indicative of a net tubular secretion. Administration of probenecid resulted in a significant rise in PSA and in a significant decrease in urinary excretion but with no change in the plasma protein binding ratio. CSA decreased significantly from 2.24 +/- 0.34 to 0.71 +/- 0.14 ml/g X min. The inhibitory action of SA-446 (0.02 mg/kg, i.v.) on the pressor response to angiotensin I disappeared at about 50 min, this action being maintained for about 2 h in the probenecid pretreated dog. Since probenecid is a competitive inhibitor of organic anion secretory transport, our results show the net tubular secretion of SA-446, via organic anion transport systems. Prolongation of the action of SA-446, as induced by probenecid may be due to the increase of plasma concentration, by the inhibition of tubular secretion.