Chii-Ming Lai

Kinetics of esmolol, an ultra-short-acting beta blocker, and of its major metabolite

Esmolol is an ultra‐short‐acting beta blocker. Its kinetics was studied in eight healthy subjects after continuous intravenous infusion of 400 μg/kg/min over 2 hr. The concentrations of esmolol and its major metabolite, 3‐[4‐(2‐hydroxy‐3‐{isopropylamino}propoxy)phenyl]propionic acid, in blood and urine were determined by gas chromatographic‐mass spectrometric assay and HPLC. The distribution and elimination t½s of esmolol averaged 2.03 and 9.19 min. The apparent volume of distribution of esmolol averaged 3.43 l/kg and was four times the volume of the central compartment. The total clearance of esmolol averaged 285 ml/min/kg, indicating that nonhepatic routes play a predominant role in its clearance. The t½s of formation and elimination of the metabolite averaged 2.82 min and 3.72 hr. The ratio of the metabolite formation and elimination rate constants of the parent drug (kf/k10) averaged 0.829, suggesting that 82.9% of esmolol was converted to the metabolite (which is consistent with the urinary recovery of 71% of the dose as unconjugated metabolite). The volume of distribution and total clearance of the metabolite averaged 0.411 l/kg and 1.28 ml/min/kg. Esmolol was followed by a significant reduction of isoproterenol‐induced increase in heart rate and systolic blood pressure at doses of 50, 150, and 400 μg/kg/min. There was a strong correlation between the magnitude of these effects and the logarithm of the steady‐state blood concentrations of esmolol.

Pharmacokinetics of Hydroxyethyl Starch in Normal Subjects

Abstract: To determine the elimination of high‐molecular‐weight hydroxyethyl starch (HES, Mw 450,000) in normal subjects, ten volunteers were given 500 ml 6% HES solution by intravenous infusion, and serial blood and urine samples were collected for nonglucose total carbohydrate determination. On the average, 46 and 64 per cent of the dose was excreted in the urine within two and eight days, respectively. The plasma concentration declined rapidly during the first week after infusion. The average terminal half‐life was 17 days during the first 42 days, which accounted for elimination of about 90 per cent of the dose. The remainder was eliminated with a terminal half‐life of 48 days determined between days 42 and 83 of the study. As expected, the infusion of HES resulted in plasma volume expansion over a 48‐hour period during which time levels of nonglucose carbohydrates were above 3.5 mg/ml. HES is metabolized by α‐amylase in the body. During the first 48 hours after infusion of HES, plasma α‐amylase activity was significantly increased over control. Concomitantly, α‐amylase activity in urine was also elevated but not significantly so.

Chemical characterization of the persistent fraction of hydroxyethyl starch in rat serum and spleen

Hydroxyethyl starch (HES) found in rat serum and spleen after single and daily administrations of 0.9 g/kg for 1 week was characterized by gas-liquid chromatography. There was very little difference in the degree of substitution (D.S.) and molar substitution (M.S.) of HES in serum samples obtained at 1 hour and 57 days after multiple doses and of HES in spleen samples obtained at 1 hour and 168 days after a single dose of HES. The small increase in D.S. and M.S. was due to a decrease in the glucose content and not due to a change in the ratio of mono- to poly-substituted glucoses.

Disposition study of procainamide and N-acetylprocainamide during subacute administration in rats.

Abstract The purpose of this investigation was to study the disposition of procainamide (PA) and N-acetylprocainamide (NAPA) during repeated administration to male and female Charles River CD rats. Both drugs were administered in the diet for 8 weeks at doses of (320, 1280, and 2560 mg/kg/day). Plasma and urine samples were collected from each animal after 2 and 8 weeks of dosing for up to 48 hr. PA and NAPA concentrations in plasma and urine samples were determined by specific high-pressure liquid chromatographic methods. The plasma concentration-versustime profile showed highest plasma concentrations at midnight and lowest concentrations at 6 pm , suggesting that food consumption was greatest between 6 pm and midnight. On the average, 16 and 51% of the estimated doses of PA and NAPA, respectively, were excreted unchanged in urine in both sexes. In the animals which received PA, the ratio of unchanged drug excreted in urine to its acetylated form, i.e., NAPA, increased with an increase in the dose, suggesting saturation of the acetylation process and confirming the dose-dependent kinetics of PA elimination in rats. Within the dose range administered in this study, the elimination kinetics of NAPA was linear. The results of this work showed that PA and NAPA toxicity studies could be conducted by dietary administration.