Pharmacokinetic-Pharmacodynamic Relations of Losartan and EXP3174 in a Porcine Animal Model

Abstract

The pharmacokinetics of losartan and EXP3174, an active metabolite of losartan, were evaluated in the anesthetized pig after both a single intravenous dose (3 mg/kg) and during constant intravenous infusion. The pharmacodynamic activities of losartan and EXP3174 were determined during constant intravenous infusion as the degree of inhibition of angiotensin II-induced increase in the diastolic pressure. The systemic plasma clearance of losartan was 22.1 +/- 4.4 ml/min/kg (mean +/- SEM) and had an apparent volume of distribution at steady state of 0.56 +/- 0.16 L/kg after a 3-mg/kg intravenous dose. The elimination half-life of losartan was 40 +/- 6 min. Less than 2% of the intravenous losartan doses was estimated to be present as unconjugated EXP3174. The plasma clearance of EXP3174 was approximately 50% that of losartan, 11.8 +/- 1.5 ml/min/kg, and had a smaller steady-state apparent volume of distribution, 0.18 +/- 0.04 L/kg. The elimination half-life for EXP3174 was slightly longer than that of losartan (52 min). The time course of the pharmacodynamic effects of losartan and EXP3174 closely followed their respective plasma concentrations. The apparent dissociation constant of EXP3174 to the angiotensin II receptor was estimated, based on the total plasma concentrations, to be approximately 5 times lower than that for losartan.

Species Differences in the Pharmacokinetic Parameters of Cytochrome P450 Probe Substrates between Experimental Animals, such as Mice, Rats, Dogs, Monkeys, and Microminipigs, and Humans

“…Thus, we assessed the activity of CYP2C using both losartan and omeprazole, which are metabolized to EXP3174 and 5-hydroxyomeprazole by CYP2C9 and CYP2C19 mainly, respectively [46,47]. The oxidative conversion of losartan to EXP3174 is also observed in rats, dogs, monkeys, and pigs [46,[48][49][50]. The BA of losartan in humans was previously reported to be 35.8% [51].…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…C). In pigs, only 2% of an administered losartan dose becomes detectable in the circulation as nonmetabolized EXP3174 (Lankford et al, 1997). Such interspecies differences need to be taken into consideration when interpreting pharmacological data from experimental animals.…”

Role of angiotensin II under prolonged increased intraabdominal pressure (IAP) in pigs

“…The amount of drug used for bolus injection was dissolved in 10 ml saline, and that used for continuous infusion was dissolved in 45 ml saline and infused at a rate of 10 ml per hour. The dose was based on the pharmacological study by Lankford et al [14].…”