Pharmacokinetics of Temocapril and Enalapril in Patients with Various Degrees of Renal Insufficiency

Abstract

Temocapril is a novel ACE inhibitor that is cleared via dual excretion routes in humans. Borderline or mildly hypertensive patients with normal renal function [group 1, creatinine clearance (CLCR) > 70 ml/min (4.2 L/h), n = 12], moderate renal impairment [group 2, CLCR 30 to 70 ml/min (1.8 to 4.2 L/h), n = 12] or severe renal impairment [group 3, CLCR < 30 ml/min (1.8 L/h), n = 12] received a single oral dose of either temocapril 1 mg (n = 6, each group) or enalapril 5mg (n = 6, each group). These 2 drugs gave similar values for the area under the plasma concentration-time curve (AUC) of the active diacids. The maximum plasma concentration of enalapril diacid was increased 2- and 6-fold in moderate and severe renal impairment, respectively, whereas that of temocapril diacid was not altered. The AUC of enalapril diacid increased 13-fold at CLCR values < 30 ml/min, but that of temocapril diacid increased only 2-fold. The duration of plasma ACE inhibition due to enalapril was greatly prolonged by the impairment of renal function, whereas that due to temocapril was affected very little. Urinary recovery of temocapril diacid was decreased markedly in patients with severe renal dysfunction, most probably because the diacid was excreted through the biliary route. On the other hand, urinary recovery of enalapril diacid remained fairly high even in patients with severe renal impairment, because of extremely high plasma diacid concentrations resulting from the lack of biliary excretion. These observations suggest that temocapril is beneficial in the treatment of hypertension in patients with severely impaired renal function.

Impact of Drug Transporter Studies on Drug Discovery and Development

“…They are excreted predominantly into the urine. In contrast, temocaprilat is excreted via both bile and urine (Oguchi et al, 1993). (Jonker et al, 2001) 14 C concn (ngϪeq g Ϫ1 or ml …”

“…In such patients, the AUC and C max values of captopril and enalapril are markedly increased because these ACE inhibitors are eliminated primarily via renal excretion (Oguchi et al, 1993). In contrast, alterations in these pharmacokinetic parameters are minimal for temocaprilat because of the presence of the biliary excretion pathway (Oguchi et al, 1993). A multiple elimination pathway will result in a relatively stable pharmacokinetic profile compared with only a single elimination pathway.…”

Transporters for Bile Acids and Organic Anions

“…In patients with renal failure, the area under the curve (AUC) and C max of captopril and enalapril are markedly increased, so it is necessary to reduce the dosage and/or to change the dosage interval because these ACE inhibitors are eliminated primarily via renal excretion (Lowenthal et al, 1985;Sica, 1992). In contrast, alterations in these pharmacokinetic parameters are minimal for temocaprilat because of the presence of the biliary excretion pathway (Oguchi et al, 1993). In order to examine the mechanism for the efficient biliary excretion of temocarpilat, the hepatocellular transport of this compound was examined.…”

Prediction of the Hepatic and Renal Clearance of Transporter Substrates in Rats Using in Vitro Uptake Experiments

“…Therefore, to avoid large changes in the pharmacokinetics of drugs in unusual circumstances, clearance from multiple elimination pathways in liver and kidney is thought to be a desirable feature for many drugs. For example, the plasma concentration of enalaprilat was significantly increased by reduced renal function, whereas that of temocaprilat was not significantly changed (Oguchi et al, 1993) because enalaprilat is predominantly excreted from the kidney, whereas temocaprilat is excreted from both the liver and kidney, which can minimize the effect of renal dysfunction because of its alternative elimination route by the liver (Ishizuka et al, 1997(Ishizuka et al, , 1998. On the other hand, if the pharmacological target is the liver or kidney, efficient targeting of drugs is needed to maximize the pharmacological effect.…”