Clinical Pharmacokinetic Considerations in the Use of Plasma Expanders

Summary

This review deals with the pharmacokinetics of dextrans and hydroxyethylstarch, the most commonly used plasma expanders. The complex composition of these colloidal agents (broad range of molecular weight distribution in vitro and in vivo, ) confounds their specific assay and meaningful pharmacokinetic analysis. In addition, the time-dependent decline of plasma concentrations of the plasma expanders is at least biphasic, and in some clinical studies the time period for plasma concentration monitoring has been inadequate to characterise the terminal elimination phase.

According to their average molecular weight, dextrans can be differentiated into dextran 1, dextran 40, dextran 60 and dextran 70. Metabolism of dextrans by dextranases and extrarenal excretion account for only 2 to 10% of the overall drug loss from the body. Persistence of dextrans in the systemic circulation and elimination by the renal route are dependent on the size of dextrans and their molecular weight distribution. Dextran species with a molecular weight below 15,000 daltons are filtered unrestricted, and consequently the elimination half-life of dextran 1 is relatively short (2 hours) and that of dextran 40 (10 hours) or dextran 60 (42 hours) much longer. In patients with renal insufficiency elimination is impaired in parallel to the reduction in glomerular filtration rate, and smaller doses are advisable in these patients. Dosage reduction might be also indicated if multiple infusions of dextrans are used, since dextran 40 accumulates considerably during long term use (particularly the fractions with higher molecular weights). As only about 50 to 70% of a single dose could be recovered within 48 hours in the urine, the remainder of the dose is probably stored somewhere in the body.

Disposition of hydroxyethylstarch is dependent on 2 major factors. As with dextrans, the molecular weight distribution affects the rate of renal elimination. In addition, the degree of substitution with hydroxyethyl groups mainly determines the metabolism of hydroxyethylstarch by α-amylase, and thus the overall elimination rate. A higher molecular weight range (e.g. hydroxyethylstarch 450,000 vs 200,000) and a more extensive degree of substitution (e.g. 0.7 vs 0.5) result in a slower elimination, as can be seen by comparing the half-life values of hydroxyethylstarch 450/0.7 (48 days) and hydroxyethylstarch 200/0.5 (20 days). Since only 40 to 65% of an infused dose could be recovered in the urine in humans, the remainder of the dose may be stored in the body. Animal experiments suggest that certain fractions of hydroxyethylstarch might be stored in some tissues. However, during multiple infusions with hydroxyethylstarch 200/0.5 for 10 days no accumulation was observed in the plasma of patients.

In conclusion, the disposition and pharmacological effects of plasma expanders are related to time-dependent changes in the molecular weight distribution of the plasma concentration decline. Unfortunately, the analytical assays applied in most studies were not able to differentiate the complex mixture of the infused colloids.