Oral and intravenous pharmacokinetics of milrinone in human volunteers.

Thirty-nine healthy men received milrinone either orally or intravenously in two separate double-blind, placebo-controlled studies. The mean bioavailability, based on the area under the plasma concentration versus time curves, was 0.92. The plasma data for those subjects in the intravenous study were described by an open two-compartment model with a mean (+/- SD) apparent first-order terminal elimination rate constant (beta) of 0.86 (+/- 0.23) h-1, which corresponds to a half-life of 0.8 h. In the intravenous study, the renal clearance and total body clearance were 21.1 and 25.9 L/h, respectively. The corresponding values in the oral study were 23.8 and 29.7 L/h. Between 79.9 and 84.5% of the total doses were recovered in the urine samples taken at 0-24 h.

Correlation of the hemodynamic and pharmacokinetic profile of intravenous milrinone in the anesthetized dog.

The relationship between the hemodynamic effects of milrinone and its plasma concentration was studied in the anesthetized instrumented dog. Milrinone was administered intravenously either as a single bolus of 10, 30 or 100 micrograms/kg or infused at a rate of 10 micrograms/kg/min. The changes in drug plasma concentration and cardiovascular parameters were determined simultaneously during the course of drug action. The intravenous bolus injections of milrinone caused dose-dependent increases in its maximum plasma concentration that resulted in concomitant increases in both cardiac contractile force and heart rate with simultaneous decreases in systolic and diastolic blood pressure. The intravenous infusion of milrinone caused parallel increases in both drug plasma concentration and cardiac contractile force; following termination of the milrinone infusion, there was a gradual decline in both its plasma concentration and in its inotropic activity, with a similar time course for these two parameters. A positive correlation (r = 0.78; p less than 0.008) was obtained between milrinone plasma concentration and its inotropic effect.

Relationship between amrinone plasma concentration and cardiac index.

Amrinone was given to 14 patients with congestive heart failure as an intravenous bolus (1 mg/sec) at doses ranging from 0.5 to 3.5 mg/kg. Simultaneous determinations of cardiac index were made by thermodilution and of amrinone plasma concentration by high-performance liquid chromatography. A relationship between improvement in cardiac index and increasing plasma concentrations of amrinone was demonstrated for 13 of the 14 patients. The percentage increase in cardiac index correlated with amrinone plasma concentration (r = 0.81; p less than 0.001). Amrinone was given to four patients as an intravenous bolus dose of 1.5 mg/kg followed by a constant infusion of 10 micrograms/kg/min for 10 hr; simultaneous determinations of cardiac index and circulating levels of amrinone indicated that both declined after the initial rise. The plasma concentration of amrinone remained relatively constant during the infusion at about 1.7 micrograms/ml. In all cases, despite the relatively constant plasma levels there was a decline in cardiac index after about 4 to 5 hr of infusion, although the cardiac index remained above the baseline; during the constant infusion the cardiac index rose again and was maintained at a reasonably constant level for the last 3 hr. Seven patients received oral doses of amrinone of about 3 mg/kg, and simultaneous determinations of cardiac index and plasma concentration showed a relationship between amrinone level and rise in cardiac index (p less than 0.05). In 16 patients after amrinone orally sufficient blood samples were taken to estimate the apparent first-order terminal elimination t 1/2. The t 1/2 as estimated by log-linear regression ranged from about 3 to 15 hr; mean +/- SEM value was 8.3 (+/- 1.1) hr.

Amrinone metabolism.

High-performance liquid chromatographic methods for the analysis of amrinone in plasma and for both amrinone and its N-acetyl metabolite in urine were developed and applied to measure specimens obtained from a number of healthy men who had received intravenous or oral amrinone. The intravenous doses ranged from 0.8 to 2.2 mg/kg. Terminal elimination of amrinone from the bloodstream followed apparent first-order kinetics. Half-life, after the drug had distributed to the tissues, was estimated by a log-linear least-squares regression; mean half-life was 2.6 +/- 1.4 hr. During the first 24 hr after medication, unchanged amrinone excreted in the urine of these subjects represented 10% to 40% of the dose. N-Acetyl metabolite in the urine represented less than 2% of the dose. In the oral study, doses ranged from 25 to 250 mg (0.31 to 3.5 mg/kg) and the maximum plasma concentration attained was proportional to the dose. The first order terminal elimination half-life was possibly dose-related. In only one subject were there unequivocal amounts of the N-acetyl metabolite in the plasma.

Analysis of iosulamide in plasma and urine: application to intravenous pharmacokinetics in rhesus monkey.

A sensitive, specific, high-performance liquid-chromatographic method for the determination of iosulamide in plasma and urine is described. The method was used to determine pharmacokinetic parameters of iosulamide after intravenous administration to rhesus monkeys. The mean (+/- SE) distribution and disposition half-lives were 0.19 (+/- 0.03) and 1.5 (+/- 0.3) hr, respectively. The mean (+/- SE) model-dependent and model-independent volumes of distribution at steady state were 0.41 +/- (0.078) and 0.49 (+/- 0.039) liters/kg, respectively. Total urinary excretion of iosulamide represented a mean (+/- SE) of 12.5 (+/- 0.6)% of the administered dose and was virtually complete in 3 hr. The results of the pharmacokinetic study indicate that iosulamide is rapidly cleared from the body and that renal clearance is a minor route of elimination from the body.