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Abstract: To determine the elimination of high‐molecular‐weight hydroxyethyl starch (HES, Mw450,000) 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.

Hetastarch, ethoxylated amylopectin, has found clinical utility as a plasma volume expansion agent, a sedimenting agent during pheresis, and a pump priming fluid. Hetastarch is a complex mixture of derivatized amylopectin molecules of various molecular sizes. The derivatization causes resistance to enzymatic hydrolysis, therefore, allowing hetastarch sufficient vascular residence time to be an effective vascular osmotic agent. This has led to its use as a volume expander and to its consequent use as a pump priming fluid. The metabolism of hetastarch proceeds through α-amylase hydrolysis of glycosidic bonds, yielding molecules small enough for renal clearance, but does not result in complete hydrolysis. Hence, glucose is not a significant product of hetastarch metabolism. Metabolism proceeds at such a rate that volume expansion is seen for 24–36 hours with a maximum effect (100–172 percent of the infused volume) occurring shortly after infusion. Ninety percent of the dose is eliminated with a half-life of about 17 days.

Esmolol is an intravenous beta blocker with a short duration of action. The pharmacokinetics of esmolol and its acid metabolite, ASL‐8123, were studied in nine patients who had stable, biopsy‐proved Laennec's cirrhosis and in three normal volunteer controls. Kinetics were determined after a four‐hour continuous infusion of esmolol at a rate of 200 μg/kg/min. Blood samples were collected during the infusions and at frequent intervals thereafter. The parameters studied were the steady state concentration, the total body clearance, the elimination half‐life, the area under the curve, and the volume of distribution. No significant differences in any of these parameters were detected between control subjects and those with hepatic disease, for either esmolol or its acid metabolite. It is concluded from this study that Laennec's cirrhosis does not cause any change in the pharmacokinetics of esmolol or its major metabolite. Therefore, adjustments in dosage of esmolol are not required for patients with Laennec's cirrhosis.

More efficient drug and biologics development is necessary for future success of pharmaceutical and biotechnology companies. One way to achieve this objective is to use rationally selected surrogate markers to improve the early decision‐making process. Using typical clinical chemistry methods to measure biochemical markers may not ensure adequate precision and reproducibility. In contrast, using analytical methods that meet good laboratory practices along with rational selection and validation of biochemical markers can give those who use them a competitive advantage over those who do not by providing meaningful data for earlier decision making.

The pharmacokinetics and pharmacodynamics of flestolol, a new short‐acting, beta‐adrenergic receptor antagonist, were examined in nine healthy subjects after a constant intravenous infusion of 5 μg/kg/min for 72 hours. Flestolol blood levels were determined by high‐performance liquid chromatography. In all subjects, flestolol blood concentration attained steady state 30 minutes after initiation of infusion. The mean ± standard deviation steady‐state concentration of flestolol was 31.1 ± 12.0 ng/mL. The elimination half‐life averaged 7.2 minutes. The mean ± standard deviation total body clearance was 181 ± 66 mL/min/kg. The apparent volume of distribution and the area under the curve averaged 1.89 L/kg and 2.23 μg‐hr/mL, respectively. Flestolol did not cause any significant change (P> .05) in the heart rate or systolic or diastolic blood pressure from the baseline. Flestolol significantly (P< .05) attenuated the isoproterenol‐induced increase in heart rate and systolic blood pressure and decrease in diastolic blood pressure in comparison with baseline. The average maximum reduction in isoproterenol tachycardia was in the range of 63% to 79% during flestolol infusion. There was a rapid recovery from beta blockade after termination of flestolol infusion; the recovery averaged 96% 20 minutes after the infusion was stopped. We conclude that flestolol exhibits a very short half‐life and is cleared mainly by extrahepatic routes. It is an effective beta blocker and possesses a short duration of action.

The effect of renal function on the pharmacokinetics of esmolol, an ultra-short-acting β-adrenergic blocker, and its major metabolite, ASL-8123, was examined in six healthy control subjects, six patients maintained on hemodialysis, and six patients on continuous ambulatory peritoneal dialysis (CAPD). In addition, the impact of hemodialysis and CAPD on removal of esmolol and ASL-8123 was determined. Multiple blood, urine, and dialysate samples were collected during a 72-hour period and assayed for esmolol and ASL-8123 by HPLC. The pharmacokinetic disposition of esmolol was not significantly altered by renal failure. Mean (±SD) total body clearance for esmolol was 171.4 ± 69.8, 249.8 ± 176.3, and 265.3 ± 143.1 ml/min/kg for the control, hemodialysis, and CAPD patients, respectively. Mean elimination half-life (t½was 7.2 minutes in control subjects compared with 7.1 and 8.0 minutes for the hemodialysis and CAPD groups, respectively. The apparent volume of distribution of esmolol did not differ significantly among the three groups. ASL-8123 was shown to accumulate in patients with renal failure, as evidenced by a mean maximum blood concentration of 42.8 ± 12.2 µg/ml in the control group compared with 76.1 ± 23.9 and 87.1 ± 20.4 µg/ml in the hemodialysis and CAPD groups, respectively (p < 0.05). The elimination t½of ASL-8123 was prolonged in patients with renal failure, averaging more than 42 hours compared with only 4 hours in the control subjects. Approximately 20% of the esmolol dose as ASL-8123 was removed by either hemodialysis or CAPD, contributing minimally to the elimination of the drug. Hemodialysis clearance averaged 76.8 ml/min for ASL-8123, and mean net peritoneal dialysis clearance was only 2.7 ml/min. ASL-8123 has shown very limited β-blocking activity in animals and human beings and its toxicity is currently unknown. Based on these results, esmolol dosage would probably not require adjustment in patients with renal failure maintained on hemodialysis or CAPD.Clinical Pharmacology and Therapeutics (1989) 45, 321–327; doi:10.1038/clpt.1989.35