A semiclosed loop, bedside insulin infusion system using a simple basal infusion algorithm consisting of a linear transition between two insulin delivery rates as blood glucose (BG) increases has been developed. A theoretical study using computer simulation has now been undertaken to examine the effect of BG sampling frequency and algorithm parameters on BG control. A model for BG control by exogenous insulin in the individual with diabetes was developed from a model for healthy subjects and from clinical data in the literature. Results of computer simulation using this model showed a decrease in BG stability as the sampling interval increased from 1 to 4 h. Simulations also showed a decrease in BG stability as the sensitivity of the control algorithm increased. Choice of an appropriate basal control algorithm involved a compromise between stability, sampling interval, and metabolic control. We conclude that satisfactory metabolic control can be obtained using intermittent BG sampling in the basal state; sampling at intervals of 3 h combined with a basal control algorithm whereby insulin delivery rate increases linearly from 0.5 to 2.5 U/h over the BG range 2-12 mmol/L appears suitable for most diabetic persons. Three-hour sampling offers a good compromise between degree of metabolic control and clinical effort involved.

For substances eliminated from blood by the liver, the effect of a change in unbound fraction of drug (fu(b)) on steady state total (Cb) and unbound (Cu(b)) blood concentrations has hitherto only been considered for the two limiting cases, i.e., at the upper and lower extremes of hepatic intrinsic clearance (CL(int)). For a substance of very low CL(int), if fu(b) changes, Cb will change and Cub will remain constant, whereas if CL(int) is very high, Cub will change and Cb will remain constant. The present study defines the effects of a change in fu(b) on Cb and Cub over the whole CL(int) range. Computer simulations were undertaken which predicted that, for a given change in fu(b), absolute and relative changes in Cb would decrease nonlinearly with increasing CL(int), while the relative change in Cub would increase with CL(int). The absolute change in Cub would be independent of CL(int). Significant changes in Cb and Cub would be observed at intermediate values of CL(int) not just at the high and low extremes. These theoretical predictions were investigated experimentally in the isolated perfused rat liver by examining the effects of a change in fu(b) of sodium taurocholate a substance with intermediate CL(int) (such that at fu(b) = 0.27, hepatic extraction ratio = 0.71) induced by concurrent administration of sodium oleate. Sodium 24-14 C-taurocholate (specific activity 52 microCi/mmol) was infused into the reservoir in a recycling system at 30 mumol/hr for 105 min (n = 6). At 45 min a bolus dose of sodium oleate (50 mmol) was administered to the reservoir, followed by a constant infusion of 143 mmol/hr for 1 hr. Following the administration of oleate, taurocholate fu(b) fell promptly by 55% (0.27-0.12). There was a relative increase of taurocholate Cb of 22.7% and a relative decrease in Cub of 45.4%, in accordance with the simulations (p less than 0.05). We conclude that important changes in unbound steady-state concentration, the pharmacologically active moiety, can occur upon changes in unbound fraction with compounds of intermediate hepatic intrinsic clearance.

In the past, various models have been developed to allow better characterization of the hepatic elimination of substrates from plasma. In this study we investigated the applicability of the venous equilibrium, undistributed sinusoidal, several distributed sinusoidal, and dispersion models to the steady state elimination of sodium taurocholate by the isolated perfused rat liver. Rat livers were perfused with 24-14C-taurocholate (sodium salt) at a concentration of 25 microM (specific activity 500 microCi/mmole) in a single-pass design (n = 7) or at a rate of 0.5 mumol/min (specific activity 40 microCi/mmole) into the portal vein in a recirculating design (n = 5). In single-pass experiments, the changes in hepatic venous outflow concentration (C0) with changes in unbound fraction of taurocholate (fu) from 0.09 to 1.0 were fitted better by the venous equilibrium model, by the dispersion model, and by a distributed model in which heterogeneity in both hepatic blood flow (Q) and intrinsic clearance (CLint) was defined by separate density functions. The very large value of dispersion number (DN greater than 10(7] yielded by the dispersion model is consistent with a high degree of axial mixing of blood within sinusoids. The large coefficients of variation (0.7-232) for the density functions describing the transverse heterogeneity of Q and CLint obtained with the Q/CLint-distributed model were consistent with a large degree of heterogeneity in Q and CLint within the liver. In recirculation experiments, the steady state unbound concentration of taurocholate in the reservoir (Cuss) was independent of fu (range 0.05-0.9). This finding was not predicted by the undistributed sinusoidal model, but was in keeping with the venous equilibrium model, with the dispersion model, and with the Q/CLint-distributed model. Therefore, there is no need to invoke cell surface-mediated dissociation of albumin-ligand complexes in hepatic taurocholate uptake. As the dispersion and Q/CLint-distributed models are conceptually plausible and operationally accurate, it may be time to relinquish the venous equilibrium model, which, though operationally accurate, is conceptually flawed.

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