Determinants of [ 13 N]ammonia kinetics in hepatic PET experiments: a minimal recirculatory model

Weiß, Michael; Roelsgaard, Klaus; Bender, Dirk; Keiding, Susanne

doi:10.1007/s00259-002-0970-7

Cited by 7 publications

(7 citation statements)

References 15 publications

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“…However, the mechanism underlying this effect remains to be established. Note, furthermore, that our RD s 2 estimate for antipyrine, 3.7 Ϯ 0.5, is close to that of 2.9 for [ 13 N]ammonia in pigs (35), another indicator undergoing flow-limited distribution.…”

Section: Relative Dispersion In Systemic Circulationsupporting

confidence: 63%

“…Apart from providing a better quantitative understanding of the determinants of whole body distribution of solutes, this approach allows to study the effect of disease states not only on physiological distribution volumes but also on the underlying distribution kinetics of the respective indicators. The results obtained here for the indicators inulin and antipyrine also provide information on distribution kinetics of, for example, insulin (24) and ammonia (35), thus suggesting that the uptake rate of insulin into skeletal muscle (which mainly determines CL M ) is independent of flow, whereas the distribution clearance of ammonia is proportional to cardiac output. Given the information provided by RD 2 , the model may find application in other fields, such as analysis of noninvasively measured cardiopulmonary TTDs (23).…”

Section: Comparison Of Modelsmentioning

confidence: 71%

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Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity

Weiß

Krejcie²,

Avram³

2006

American Journal of Physiology-Heart and Circulatory Physiology

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We present an in vivo method for analyzing the distribution kinetics of physiological markers into their respective distribution volumes utilizing information provided by the relative dispersion of transit times. Arterial concentration-time curves of markers of the vascular space [indocyanine green (ICG)], extracellular fluid (inulin), and total body water (antipyrine) measured in awake dogs under control conditions and during phenylephrine or isoproterenol infusion were analyzed by a recirculatory model to estimate the relative dispersions of transit times across the systemic and pulmonary circulation. The transit time dispersion in the systemic circulation was used to calculate the whole body distribution clearance, and an interpretation is given in terms of a lumped organ model of blood-tissue exchange. As predicted by theory, this relative dispersion increased linearly with cardiac output, with a slope that was inversely related to solute diffusivity. The relative dispersion of the flow-limited indicator antipyrine exceeded that of ICG (as a measure of intravascular mixing) only slightly and was consistent with a diffusional equilibration time in the extravascular space of approximately 10 min, except during phenylephrine infusion, which led to an anomalously high relative dispersion. A change in cardiac output did not alter the heterogeneity of capillary transit times of ICG. The results support the view that the relative dispersions of transit times in the systemic and pulmonary circulation estimated from solute disposition data in vivo are useful measures of whole body distribution kinetics of indicators and endogenous substances. This is the first model that explains the effect of flow and capillary permeability on whole body distribution of solutes without assuming well-mixed compartments.

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Section: Relative Dispersion In Systemic Circulationsupporting

confidence: 63%

Section: Comparison Of Modelsmentioning

confidence: 71%

Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity

Weiß

Krejcie²,

Avram³

2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…89 The transient concentration difference between arterial and peripheral venous blood concentration, on the other hand, have to be taken into account in PK/PD modeling.…”

Section: Nonhomogeneous Sampling Compartmentmentioning

confidence: 99%

Advanced pharmacokinetic models based on organ clearance, circulatory, and fractal concepts

Pang

Weiß

Macheras

2007

AAPS J

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Three advanced models of pharmacokinetics are described. In the fi rst class are physiologically based pharmacokinetic models based on in vitro data on transport and metabolism. The information is translated as transporter and enzyme activities and their attendant heterogeneities into liver and intestine models. Second are circulatory models based on transit time distribution and plasma concentration time curves. The third are fractal models for nonhomogeneous systems and non-Fickian processes are presented. The usefulness of these pharmacokinetic models, with examples, is compared.

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“…Tissues that constitute a considerable mass of the mammalian body such as muscles, skin, adipose, and bone may be included as reservoir tissues. Examples of minimal PBPK models for particular applications have been presented in literature [22][23][24][25][26]. A lumping principle stating that only dynamically similar tissues should be lumped together was derived [27].…”

Section: Model Structure Specificationmentioning

confidence: 99%

“…A modern approach based on implementation of linear system analysis (LSA) principles in physiological models has been applied to describe the disposition of several therapeutic agents [25,26,[96][97][98][99][100]. This approach aims at reducing the complexity of the classical PBPK models by keeping restrictive assumptions to the minimum.…”

Section: Systems Analysis and Physiological Modelsmentioning

confidence: 99%

A pharmacokinetic receptor-based recirculation model for target-mediated disposition drugs

Elkomy¹

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Physiologically based pharmacokinetic (PBPK) models, also known as recirculation models, consist of a series of tissue and organ blocks linked together by blood circulation, mimicking the anatomical structure of mammalian body. Each tissue is divided into vascular, interstitial, and intracellular sub-compartments. Linear system analysis (LSA)-recirculation models differ from the classical PBPK model in that they characterize each organ or tissue with a unit impulse response in the framework of inputoutput convolution relationship rather than systems of differential equations. Targetmediated disposition (TMD) is a phenomenon where drug disposition is influenced by capacity-limited binding to a target, resulting in dose-dependent events, such as a decrease in drug clearance with increasing dose level. Erythropoiesis stimulating agents such as recombinant human erythropoietin (EPO) and Continuous Erythropoietin Receptor Activator (C.E.R.A.) exhibit TMD where their disposition and anti-anemic activity are mediated by their interaction with EPO receptor (EPOR). The objectives of this work were: 1) to develop a minimal, receptor-based LSArecirculation model, 2) to apply the developed model in analyzing the effect of bone marrow (BM) ablation on C.E.R.A. elimination kinetics, and comparing EPO and C.E.R.A. interaction with EPOR in vivo, 3) to investigate the efficiency of the experimental design used to achieve the previous objective for estimation of the developed model parameters, and 4) To identify the physiological conditions at which TMD-compartmental models approximate TMD-recirculation models. A literature review of LSA-recirculation models is provided in Chapter 2. In Chapter 3, receptor-based, LSA-recirculation model was mathematically formulated, and applied to analyze C.E.R.A. pharmacokinetics studied in adult sheep with normal and ablated BM using a tracer interaction method (TIM). In Chapter 4, the model developed in Chapter 3 was further applied to analyze EPO and C.E.R.A. TIM data collected in adult sheep. A comprehensive, sensitivity analysis was performed in Chapter 5. In Chapter 6, statistical moments of linearized receptor-based compartmental and recirculation models were computed; and simulation of plasma drug concentrations, and receptor profiles in both structures were presented. The developed model, together with the TIM, was able to quantitatively assess the interaction of C.E.R.A. with hematopoietic and non-hematopoietic EPOR population and provide a mechanism based explanation for C.E.R.A.'s slower elimination and greater erythropoietic activity in vivo compared to EPO, despite its lower affinity to EPOR. The TIM detected a saturable interaction between C.E.R.A. and non-hematopoietic EPOR which contradicts the behavior of EPO. The TIM experimental setting is adequate for estimation of the developed model parameters. TMD-recirculation models reduce to TMD-compartmental models under conditions of well-perfused target tissue, comparable drug initial distribution volume and target tissue extracellu...

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Determinants of [ 13 N]ammonia kinetics in hepatic PET experiments: a minimal recirculatory model

Cited by 7 publications

References 15 publications

Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity

Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity

Advanced pharmacokinetic models based on organ clearance, circulatory, and fractal concepts

A pharmacokinetic receptor-based recirculation model for target-mediated disposition drugs

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