Urinary excretion kinetics of hydroxyethyl starch 350/0.60 in normovolaemic man.

Rates of urinary excretion concomitant with the molecular size distribution of filtered polymer fragments were determined in five normovolaemic men dosed with 30 g/m2 BSA of a species of HES (HES 350/0.60) possessing a M-W of 350 000 combined with an MS of 0.60. Approximately 13% of the total injected dose of HES 350/0.60 was excreted in urine 1 hr after dosing, and 45% by 72 hours. Gel filtration of Sepharose CL-4B revealed that aliquots of urine collected 1 hour after injection contained polymer fragments of HES 350/0.60 with values of Kav ranging between 0.88 and 0.84, and possessed a Stokes radius (r = 32A) similar to that of Dextran 20 (M-W 22 700). Polymer fragments of HES 350/0.60 excreted 6 to 48 hours after dosing, however, possessed a Kav ranging between 0.78 and 0.73 with a Stokes radius (r = 45A) similar to that of Dextran 40 (M-W 41 000). All filtered polymer fragments were less polydisperse relative to both the injection solution (Kav 0.60) and residual material recovered from blood immediately after injection (Kav 0.72). These data support the hypothesis that the excretion of HES 350/0.60 occurs in two distinct phases: a rapid phase of elimination dependent on the M-n of the injected solution, and a slower phase dependent on the MS (degree of resistance to alpha-amylase attack). This study, in conjunction with our previous investigation of the changes in circulating HES 350/0.60, define the basic differences between clearance and excretion of the dextrans and of the rapidly degraded species of HES. These data are relevant to the utilisation of HES 350/0.60 during centrifugal leucapheresis.

Changes in the molecular size distribution and post-transfusion survival of hydroxyethyl starch 350/0.60 as influenced by a lower degree of hydroxyethylation: a study in normal man.

The need to provide a greater rate of colloid clearance from blood than is presently available with the long-acting dosage form of HES 450/0.70 prompted the clinical investigation of a new species of hydroxyethyl starch (HES) possessing a M-w of 350000 concomitant with a molar substitution of 0.60 (HES 350/0.60). The concentration of HES 350/0.60 in serum fell to half its peak value in 10.2 +/- 0.7 (SD) hour (in contrast to an IT50 of approximately 25 hours with HES 450/0.70). Levels of glucose in serum remained elevated in normal fasted subjects after dosing, suggesting that catabolism of the infused HES 350/0.60 was occurring. Hydrolysis of residual HES 350/0.60 was confirmed by Sepharose CL-4B gel filtration analysis of material obtained from serum, showing continual production of smaller molecules relative to the injected solution (in contrast to HES 450/0.70, in which intermediate polymer fragments are recovered). Recovered HES 350/0.60 material displayed a Kav ranging between 0.74 and 0.72 and possessed a Stokes radius (r = 45A) similar to that of dextran 40 (M-w 41000). HES 350/0.69 appears to offer the same advantages as the currently available long-acting HES 450/0.70 but is removed from blood approximately twice as rapidly. This more rapid hydrolysis of HEs 350/0.60 may be useful, for example, in avoiding cumulative build-up of colloid in the blood of normal donors undergoing consecutive leucapheresis procedures.

The catabolism of low molecular weight-hydroxyethylated amylopectin in man. III. Further degradation of excreted polymer fragments.

Fragments of low molecular weight-hydroxyethylated amylopectin (LMW-HES) contained in the urine voided by a single normal man, 6 to 12 hours after receiving a dose of 56 g of this material, were either separated straightforwardly by gel filtration on a column of Sephadex G-200 or incubated for 18 hours at 37 degrees C in the presence of alpha-amylase contained in human saliva, and then subjected to filtration on the same column. Comparison of the two elution profiles revealed that LMW-HES material remaining in the bloodstream for 6-hours or more, had not been degraded by serum alpha-amylase to the maximum possible extent, since incubation with alpha-amylase in-vitro caused further catabolism. These data suggest that LMW-HES polymer fragments are excreted in the urine as soon as they obtain a molecular weight below the threshold of glomerular filtration.

Post-transfusion survival of hydroxyethyl starch 450/0.70 in man: a long-term study.

Intravascular persistence concomitant with changes occurring in the circulating molecular size distribution were determined in five healthy normovolaemic men dosed with 7 ml/kg of a 6% (w/v) solution of a species of hydroxyethyl starch (HES 450/0.70) possessing a M(w)- of 450 000 daltons combined with a molar hydroxyethyl group substitution (MS) of 0.70 (70 hydroxyethyl groups/100 glucose residues). The concentration of HES 450/0.70 in serum fell to 24% of its peak value (measured 2 minutes post injection) one week after the infusion. By 17 weeks after injection, < 1.0% remained in the intravascular space. The HES 450/0.70 material recovered from the bloodstream 2 minutes after injection was shown by gel filtration on a column of Sepharose CL-4B to be less polydisperse than the injected solution. The K(av) calculated for the peak of material eluted after one week showed a definite shift of molecular size toward that of a lower molecular weight composition. However, at four weeks the value of K(av) indicated a shift toward the high molecular weight region of the injected solution, and by seven weeks this movement was quite pronounced. These data clearly indicate the complex nature of the removal of HES 450/0.70 from the intravascular space of man and appear to substantiate previous clinical studies reporting that the MS plays the major role influencing the rate of elimination of this material from the bloodstream.

Catabolism of low-molecular-weight hydroxyethylated amylopectin in man. I. Changes in the circulating molecular composition.

Intravascular persistence concomitant with changes in the circulating molecular composition were determined in six fasted normal men dosed with 400 ml of 14% LMW-HES (a new plasma expander). The concentration of LMW-HES in serum fell to half its peak value in 3.9 +/- 1.1 (S.D.) hr, whereas serum levels of glucose remained elevated throughout the 12 hr postinjection fasting period. The LMW-HES recovered from the intravascular space was shown by gel filtration on a column of Sepharose CL-4B to be a narrower molecular size distribution (less polydispersion) than the injected material. The ratio of Kav . urine/Kav . injected solution was 1.34. At 30 min after injection, however, the ratio of Kav . urine/Kav . serum was 1.20, and by 24 hr, the value was 1.15. Overall, changes in the molecular distribution in the bloodstream between the end of the infusion period and 24 hr later were small. The results suggest that the intravascular catabolism of LMW-HES may occur in two distinct phases: a rapid initial degradation, followed by a more gradual elimination influenced by the MS of the injected material.

Changes in the molecular composition of circulating hydroxyethyl starch following consecutive daily infusions in man.

1 Changes in the circulating molecular composition of hydroxyethyl starch (HES) were determined in four normal men following three consecutive daily 500 ml infusions (total 1,500 ml), by passage of trichloroacetic acid filtrates of plasma through a Sepharose CL4B gel filtration column. 2 The HES recovered from the intravascular space 10 min following the injection on Days 1, 2 and 3, was of a narrower molecular size distribution than the injected material, with a noticeable shift to molecules of a low molecular weight (LMW) size. 3 The HES in the sampled plasma 24 h post-injection on Days 1, 2 and 3 consisted of molecules possessing a LMW distribution, concomitantly with a slight shift to molecules of a larger molecule size. 4 The HES recovered from the bloodstream 480 h after the third and final injection consisted of molecules possessing an intermediate size distribution, between LMW and high molecular weight (HMW) size material. 5 The results indicate that large HES molecules contained in the injected material are eliminated from the bloodstream; the HMW fraction at least partially by a alpha-amylase mediated catabolism, and the resulting LMW fraction by excretion.