Clinical applicability of current pharmacokinetic models: Splanchnic elimination of 5-fluorouracil in cancer patients

What can be inferred from limited clinical data by using current models of hepatic elimination? We examined this question by analyzing previously published data on the steady-state uptake of the anticancer agent 5-fluorouracil (5-FU) in seven cancer patients in terms of the venous equilibration model, the undistributed and distributed forms of the sinusoidal perfusion model, and the convection-dispersion model. Because of appreciable extrasplanchnic removal of 5-FU, the value of the steady infusion rate was not used in our analysis. When the data from all patients were pooled by plotting the measured hepatic venous concentration against the measured hepatic arterial concentration, the high concentration data fell on a limiting straight line of slope 1, indicating that at high dose rates elimination of 5-FU in both the liver and gastrointestinal tract was close to saturation. The intercept of this line gave a model-independent estimate of V max /Q= 48.0± 11.6 (SD) μM for the pooled data set, where V max is the maximum splanchnic elimination rate of 5-FU, and Q is the hepatic blood flow. The low concentration data points fell on a limiting straight line through the origin, from which model-dependent values of the Michaelis constant were determined. The venous equilibration model gave K m =9.4 μM , while the undistributed sinusoidal perfusion model gave K m * =26,5 μM. With these values of K m , both models fit the pooled data equally well. These methods were applied to analyses of the five individual data sets which contained sufficiently high concentration data points. The resulting mean values were V max /Q=41.0±5.1 (sem) μM, K m =8.4±1.3μM and K m * =23.2±3.2 μM. However, the splanchnic region is a highly heterogeneous organ system, for which an undistributed analysis provides no more than an upper bound on the Michaelis constant K m + ( K m + ⩽ K m * ). A perfusion model distributed to represent total splanchnic elimination is developed in the Appendix. Using previous estimates of the degree of functional heterogeneity in the liver alone, this model yields K m + values for individual patients which have a mean of 20.3±2.8 μM .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45038/1/10928_2005_Article_BF01062135.pd

Quantum theory of iconic memory

The undifferentiated event in the consciousness of an observer, introduced by von Neumann in his quantum theory of measurement, is elaborated to interpret experiments by which Sperling demonstrated iconic memory. The numerous quadruplets of letters known to Sperling's subjects implicitly but not consciously are interpreted as quantum states in a superposition reducible to any of its components by von Neumann's event in consciousness. The potential loss by decoherence of all information implicit in the superposition, and its possible retention by a secondary observer within the same organism, may be aspects of the biological evolution as of a precursor of the quantum computer

An Electrochemical Model for Depolarization of a Retinula Cell of Limulus by a Single Photon

The response of a visual cell in the eye of Limulus is treated mathematically in terms of a model derived from the properties of excitable nerve membranes. Electron microscopic sections of the rhabdomere indicate that its structure is a close-packed array of cylindrical tubules, the interiors of which communicate with the retinula cell cytoplasm, while the external interstitial fluid is a conducting medium continuous with the extracellular space of the ommatidium. If a single highly conducting channel is opened in this membrane structure, it can be shown how the excitation can spread to depolarize the retinula cell by several millivolts. Intense activity of “sodium pumps” in the rhabdomal membrane would be required to maintain the ionic concentrations in the interstitial fluid

Hepatic ICG removal in the pig depends on plasma protein and hematocrit: Evidence of sinusoidal binding disequilibrium and unstirred water layer effects

The influence of binding protein concentration and hematocrit on hepatic uptake of indocyanine green (ICG) was studied in anesthetized pigs during constant infusion of ICG. By exchange transfusions, we either substituted plasma protein with dextran 70 (n = 8) or changed hematocrit (n = 8). Intrinsic hepatic clearance of ICG, K, was calculated from plasma flow rate and concentrations in peripheral artery and liver vein after correction for extrahepatic distribution. By analyzing the relative change of K versus either the protein dilution factor or the change in plasma volume fraction (1hct), we evaluated four current models for hepatic uptake of protein-bound substances even though a number of model parameters were unknown (parameter- free testing). Protein dilution factors (unitless) of 0.506 ± 0.027, 0.673 ± 0.011, and 0.749 ± 0.028 were associated with inverse K ratios of 0.621 ± 0.025, 0.758 ± 0.021, and 0.817 ± 0.013. These data rejected the traditional hypothesis that ICG uptake is proportional to the unbound concentration. They were compatible with development of binding disequilibrium along the sinusoidal lumen, an unstirred water layer close to the hepatocyte surface, or facilitated uptake from the bound pool. A plasma volume ratio [(1-hct)/(1-hct)] of 1.14 ± 0.02 was associated with a K ratio of 1.07 ± 0.02 (P = .01). Only sinusoidal binding disequilibrium predicted this finding, whereas an additional unstirred water layer effect could not be excluded. The observations could be simulated by a model that included both of these effects. Thus, neither the relative changes of K nor the absolute K values required the assumption of facilitated uptake from the bound pool. The parameter-free design presented may be useful with other ligands in intact animals

The kinetics of continuously infused indocyanine green in the pig

Indocyanine green (ICG) is used in cardiology and hepatology for the estimation of cardiac output, liver function, and splanchnic blood flow. ICG is bound to plasma proteins and ultimately excreted by the liver. We studied the whole body kinetics of ICG during constant infusion in pigs weighing 30-40 kg. The conventional kinetic model (backflux model) assumes that deviations from one-compartmental linear kinetics is caused by backflux from a liver storage to plasma, and that no extravascular, extrahepatic distribution takes place. This model was tested against an alternative (redistribution) model postulating that temporary redistribution of ICG into an extrahepatic extravascular storage was responsible for the deviations while the hepatic uptake was a one-way first-order process. A mathematical analysis of the two models showed that they predicted different time courses of the hepatic extraction fraction of ICG. Thus, with blood sampling from both a peripheral artery and an hepatic vein, a discriminative model-testing experiment was possible. This test required a first-order steady-state hepatic removal of ICG which was confirmed in 7 experiments with infusion rates varied in a stepwise fashion (0.133 ± 0.003, 0.269 ± 0.010, 0.547 ± 0.020 and 0.130 ± 0.003 μmol · min). In the model-testing experiments (n = 10) ICG was infused at a constant rate of 0.135 ± 0.007 μmol · min. The mean concentration in peripheral artery (μM) was well fitted by the biexponential function C(t) = 0.476 · (1-0.632 · e(0.216.t)-0.368 · e(0.0172.t)). The time course of the observed hepatic extraction fraction was significantly different (p = 0.004) from that predicted from the backflux model but in agreement (p = 0.98) with the new model assuming hepatic removal to be a one-way process and implying temporary ICG redistribution into an extrahepatic, extravascular storage with an apparent volume of 0.144 ± 0.023 L · Kg. Accordingly, extravascular ICG was demonstrated in a number of different tissues after 4-hr infusion (n = 3). If ICG is used to estimate hepatic blood flow according to Fick's principle, the use of a backflux model to correct for non-steady-state conditions willlead to an overestimation of hepatic blood flow of 28% after 25-min infusion, 16% after 50 min, and 6% after 100 min. The study indicated that distribution of ICG between plasma and tissues is not instantaneous, and that the time course of the redistribution itself significantly influences whole body kinetics. Comparison with a previously published study by Ott, Keiding, and Bass of ICG kinetics after bolus injection suggested that a two-compartment model was insufficient and that the kinetics for the exchange of ICG between plasma and the redistribution space may be nonlinear. The study demonstrates how blood sampling on both sides of the eliminating organ can expose the influence of redistribution. The discriminative model test for constant infusion experiments is novel and may be useful with other ligands

Plasma elimination of indocyanine green in the intact pig after bolus injection and during constant infusion: Comparison of spectrophotometry and high‐pressure liquid chromatography for concentration analysis

Indocyanine green is used to estimate liver blood flow rate and hepatic intrinsic clearance. However, its use as a test substance for studies of liver function has been limited by two puzzling kinetic observations: a biexponential plasma decay after bolus injection with an extremely slow late phase and an apparently steadily decreasing clearance value during constant infusion. These observations have been made with spectrophotometric concentration analysis. In anesthetized 30‐to 40‐kg pigs, we examined plasma concentration curves of indocyanine green after intravenous bolus injection and during long‐term infusion. We compared spectrophotometry with high‐pressure liquid chromatography for measurement of plasma indocyanine green concentration. In freshly prepared commercially available indocyanine green, highpressure liquid chromatography could separately measure two fractions, the genuine indocyanine green (97% to 99% of total) and an in vitro degradation product (1% to 3%). Because their spectra were nearly identical, these fractions could not be distinguished by spectrophotometry. After intravenous administration both fractions were identified in the plasma by highpressure liquid chromatography. In the first series (n = 6) 25 mg of indocyanine green was injected intravenously for 5 min. When analyzed by high‐pressure liquid chromatography, the genuine indocyanine green plasma concentration decay was biexponential with rate constants 0.196 ± 0.021 (mean ± S.E.M., n = 6) and 0.0372 ± 0.0064 min. The degradation product of indocyanine green decayed almost monoexponentially, with a rate constant of 0.0093 ± 0.0002 min. With spectrophotometry a biexponential decay was observed with rate constants 0.130 ± 0.012 and 0.0095 ± 0.0001 min. The biexponential decay of indocyanine green after spectrophotometry was the result of codetermination of the two fractions: genuine indocyanine green was responsible for initial phase, and the degradation product of indocyanine green was responsible for the late phase. In the second series (n = 9), indocyanine green was administered as a constant intravenous infusion. From 90 to 240 min the intrinsic hepatic clearance of genuine indocyanine green did not change detectably with time. In contrast, the degradation product of indocyanine green never reached steady‐state concentrations. Because of codetermination of these two indocyanine green fractions, the apparent intrinsic hepatic clearance of indocyanine green estimated from spectrophotometry was steadily decreasing by 8.9% ± 1% per hour of its initial value. At the same time estimation of liver plasma flow rate based on Fick's principle was not affected by the choice of analytical methodology. These observations indicate that high‐pressure liquid chromatography is superior to spectrophotometry for kinetic analysis of indocyanine green elimination. (HEPATOLOGY 1993;18:1504–1515.) Copyrigh