Pharmacokinetics and Pharmacodynamics of Pentopril, a New Angiotensin‐Converting‐Enzyme Inhibitor in Humans

Abstract

In a single, ascending-dose tolerance study, nine healthy volunteers were given oral pentopril 50 to 750 mg (CGS 13945) in groups of three each. Disposition characteristics of pentopril and its active metabolite (CGS 13934) were determined using plasma concentration and urinary excretion data. The drug was absorbed rapidly following zero-order kinetics. The drug has an apparent volume of distribution of 0.83 L/kg and an oral clearance of about 0.79 L/hr/kg. Urinary excretions, calculated after 125- and 250-mg doses, showed a dose proportional urinary recovery of 21% (+/- 5%) for pentopril and 40% (+/- 5%) for CGS 13934. In the multiple-dose study of 125 mg orally q12h in six healthy subjects, the plasma concentrations for both drug and metabolite showed no appreciable accumulation of either compound, which was expected from their short pharmacokinetic half-lives (pentopril, less than 1 hr; CGS 13934, approximately 2 hr). In a separate pharmacodynamic study, drug and metabolite concentrations were evaluated against angiotensin-I (AI)-induced changes in blood pressure and plasma angiotensin-converting-enzyme (ACE) activity in healthy volunteers after single oral doses (range, 10-500 mg). The pharmacodynamic half-life for plasma ACE inhibition increased with the dose (10 mg, 1.5 hr; 500 mg, 9.8 hr). There was a close relationship between the plasma level of the metabolite and the inhibition of plasma ACE activity and AI-induced pressor response. A hyperbolic function adequately described the dependence of plasma ACE activity on plasma metabolite concentration with a concentration at half-maximal inhibition of 53 ng/mL.

Pharmacokinetics of Newer Drugs in Patients with Renal Impairment (Part II)

“…Pharmacokinet. 20 (5) 1991 unchanged in the urine, whereas the remaining 35 to 40% of the dose is hydrolysed to the active metabolite which is also excreted unchanged in the urine (Rakhit et al 1986). Pentopril has a very short t'l2 of 0.7h; the terminal tlh of the metabolite is longer, being 2 to 3 hours.…”

“…It does not undergo metabolism in vivo and is mainly excreted unchanged by the kidneys. The bioavailability of k Rakhit et al (1986). e Kelly et al (1986);Ulm et al (1982).…”

“…Pentopril has a large V d of 0.83 L/kg, and the plasma CL was 0.79 L/h/kg. The CLR of the parent drug and ofpentoprilat were 0.16 and 0.19 L/h/kg, respectively (Rakhit et al 1986); the t'l2 of both is relatively short compared with the dosing interval of 12h. Hence, no accumulation of these agents was observed with repeated dosing in patients with normal renal function (Rakhit et al 1986).…”

Effect of renal impairment on disposition of pentopril and its active metabolite

“…Blood and urine sampling. Serial 7 ml blood samples were collected 0, Y2, 1,195,2,3,4,5,6,8,12,16,24,36,48, and 72 hours after drug administration into heparinized tubes. Plasma was separated from blood by centrifugation and stored at -20" C until analyzed.…”

Enantioselective Synthesis of trans‐2,3‐Dihydro‐1H‐indoles Through C–H Insertion of α‐Diazocarbonyl Compounds

“…Dihydroindoles (indolines) are constituents of many natural products and biologically active compounds, such as vinblastine, physostigmine and pentopril (Figure ).…”