Distribution and kinetics of glucose in rats analyzed by noncompartmental and compartmental analysis

Abstract

The steady-state kinetics and distribution of glucose were assessed using noncompartmental and various two-compartment models in rats that were infused with insulin (+/- euglycemic clamping), methylprednisolone (MP), or phlorizin (PHL) as well as rats injected with protamine-zinc-insulin (PZI) or rendered diabetic. Decreases in clearance of glucose (PCR) were greatest with insulin infusion, followed by PHL, MP, and PZI treatments. PCR decreased in diabetes to 25% of normal. With hyperinsulinemia and euglycemia, turnover rates were 1.18 times the rate of glucose infusion. In normal rats the ratio of the contents of the two compartments was 0.6-0.8 (depending on the model). Significant increases, of between 2.8 and 5.2, were observed with insulin infusion and between 0.8 and 1.8 with PHL, again depending on the model. Because PHL-induced changes in PCR are renal, these data suggest that variations in glucose distribution depend on changes in PCR as well as insulin. The intercompartmental rate constant decreased, and the noncompartmental volume of distribution increased to reflect the above changes. In non-steady-state studies, glucose release increased in response to insulin but not to PHL in contrast to other species.

Pharmacokinetic/Pharmacodynamic Modeling of GLP-1 in Healthy Rats

“…Overall, the present model very well captured the glucose profiles. Glucose volume of distribution V glu (0.201 L/kg) and elimination rate k out_glu (0.0445 h −1 ) were both close to reported values (12,13). Despite remarkable changes of insulin concentrations among groups, the glucose concentrations were similar.…”

Population Pharmacodynamic Modeling of Exenatide After 2-Week Treatment in STZ/NA Diabetic Rats

“…The estimated parameters and intersubject variability terms are summarized in Table . All population mean parameters were estimated with good precision and are comparable with literature‐reported values . The estimated volume of the distribution of glucose is equivalent to a literature‐reported value (0.201 L/kg) when pooled data were analyzed and thus fixed in the final model.…”

Glucose effectiveness assessed under dynamic and steady state conditions. Comparability of uptake versus production components.

“…Given the preponderance of studies in which models of glucose kinetics have been applied to the IVGTT (15,17,18,(44)(45)(46), it is valid to question the contribution of the present model and its application in this study. The uniqueness of the present study lies not in the model per se, but in its application to an experimental protocol designed solely to quantify glucose effectiveness and its component factors.…”

“…We examined the possible influence of this assumption on our assessment of the relative contribution of glucose's effects on uptake and production to glucose effectiveness. We tested two alternative assumptions in the calculation of relative contributions of uptake and HGO to overall glucose effectiveness: (a) that k 02 ϭ k 01 (17,44), and (b) that k 02 /k 01 ‫ف‬ 0.3, i.e., that uptake from the second compartment is about one-third of glucose uptake from compartment 1 at basal insulin (15). The k 02 /k 01 ratio was also varied evenly from 0 to 1.2 to cover the assumptions listed above.…”

“…Two-compartment model analysis was performed for each dog using different k 02 /k 01 ratios, which were varied between 0 and 1.2 (see text). Arrows on x-axis indicate three specific assumptions tested: (a) that k 02 ϭ 0 (17, 18); (b) the assumption of 1:3 partitioning between uptake from two compartments (15); (c) that k 01 ϭ k 02 (17,44).…”