PKQuest: volatile solutes – application to enflurane, nitrous oxide, halothane, methoxyflurane and toluene pharmacokinetics

Levitt, David G.

doi:10.1186/1471-2253-2-5

Cited by 17 publications

(31 citation statements)

References 71 publications

(128 reference statements)

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“…Their tissue/blood partition is dominated by simple, non-specific partition into the tissue lipid. In a previous application of PKQuest to the volatile anesthetics [4], it was shown that the water/tissue partition could be directly determined just from a knowledge of the fraction of lipid in the different tissues and the value of lipid/water partition coefficient (K oil ). This means that once the tissue lipid fractions are known (which are not solute dependent), the tissue/blood partition coefficient for any solute of this type is completely characterized by knowledge of the just the one physical parameter, the K oil .…”

Section: Introductionmentioning

confidence: 99%

Human physiologically based pharmacokinetic model for propofol

Levitt

Schnider

2005

BMC Anesthesiol

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BackgroundPropofol is widely used for both short-term anesthesia and long-term sedation. It has unusual pharmacokinetics because of its high lipid solubility. The standard approach to describing the pharmacokinetics is by a multi-compartmental model. This paper presents the first detailed human physiologically based pharmacokinetic (PBPK) model for propofol.MethodsPKQuest, a freely distributed software routine , was used for all the calculations. The "standard human" PBPK parameters developed in previous applications is used. It is assumed that the blood and tissue binding is determined by simple partition into the tissue lipid, which is characterized by two previously determined set of parameters: 1) the value of the propofol oil/water partition coefficient; 2) the lipid fraction in the blood and tissues. The model was fit to the individual experimental data of Schnider et. al., Anesthesiology, 1998; 88:1170 in which an initial bolus dose was followed 60 minutes later by a one hour constant infusion.ResultsThe PBPK model provides a good description of the experimental data over a large range of input dosage, subject age and fat fraction. Only one adjustable parameter (the liver clearance) is required to describe the constant infusion phase for each individual subject. In order to fit the bolus injection phase, for 10 or the 24 subjects it was necessary to assume that a fraction of the bolus dose was sequestered and then slowly released from the lungs (characterized by two additional parameters). The average weighted residual error (WRE) of the PBPK model fit to the both the bolus and infusion phases was 15%; similar to the WRE for just the constant infusion phase obtained by Schnider et. al. using a 6-parameter NONMEM compartmental model.ConclusionA PBPK model using standard human parameters and a simple description of tissue binding provides a good description of human propofol kinetics. The major advantage of a PBPK model is that it can be used to predict the changes in kinetics produced by variations in physiological parameters. As one example, the model simulation of the changes in pharmacokinetics for morbidly obese subjects is discussed.

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Section: Introductionmentioning

confidence: 99%

Human physiologically based pharmacokinetic model for propofol

Levitt

Schnider

2005

BMC Anesthesiol

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“…In the case of HLVOCs, one critical determinant relates to solubility in the neutral lipid component of tissues and blood. Several authors, recognizing the critical role of lipids in determining the tissue distribution of superlipophilic compounds, Toxicology Mechanisms and Methods Downloaded from informahealthcare.com by CDL-UC Davis on 11/04/14 402 C. EMOND AND K. KRISHNAN have attempted to develop PBPK models based on tissue lipid contents (Lindstrom et al 1976;Pelekis et al 1995;van der Molen et al 1996;Levitt 2002;Emond et al 2005). The present study has, for the first time, shown that a physiological pharmacokinetic model based on neutral lipid content of tissues and blood does not require the use or estimation of tissue:blood partition coefficients and still enables adequate simulation of the uptake and disposition of HLVOCs (e.g.,and 1,2, in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Levitt (2002), using water: air and oil:water partition coefficients along with the lipid content of blood and tissues, developed PBPK simulations of the pharmacokinetics of volatile solutes in humans. The present study, considering the intrinsic liposolubility characteristics of HLVOCs, chose to represent only the volumes of NLEs in each of the tissue compartments and blood.…”

Section: Discussionmentioning

confidence: 99%

“…The solubility of highly lipophilic substances in polar lipids and water fractions of the various compartments is negligible and is explained by the relatively high n-octanol:water partition coefficients of such chemicals. Therefore, the kinetics of highly lipophilic chemicals can be simulated solely with the consideration of their solubility and distribution in neutral lipid fractions of tissues and blood (Lindstrom et al 1976;van der Molen et al 1996;Levitt 2002;Emond et al 2005). Consequently, if the volumes of the model compartments represented only the neutral lipid fraction of 396 C. EMOND AND K. KRISHNAN tissues and blood, then there is no necessity to use or estimate a tissue:blood partition coefficient since the (tissue) neutral lipid: (blood) neutral lipid partition coefficient should be unity.…”

Section: Introductionmentioning

confidence: 99%

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A Physiological Pharmacokinetic Model Based on Tissue Lipid Content for Simulating Inhalation Pharmacokinetics of Highly Lipophilic Volatile Organic Chemicals

Emond

Krishnan

2006

Toxicology Mechanisms and Methods

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The highly lipophilic volatile organic chemicals (HLVOCs) are distributed almost uniquely in the neutral lipid fraction of tissues and blood. As suggested by their high n-octanol:water partition coefficient (>1000), their solubility in water fraction of tissues and blood is negligible. Hypothetically, then, the kinetics of HLVOCs can be simulated solely with the consideration of their solubility and distribution in neutral lipid-equivalent (NLE) fractions of the tissues and blood. The objectives of the present study were therefore (i) to develop a physiological pharmacokinetic model based on NLE content of tissues and blood, and (ii) to apply this model framework for simulating the inhalation pharmacokinetics of HLVOCs (i.e., d-limonene, alpha-pinene, and 1,2,4-trimethylbenzene) in humans. The PBPK model developed in this study consisted of tissue compartments that represented only their NLE content. All biological parameters, except alveolar ventilation rate, were expressed on the basis of their NLE content. Tissue:blood partition coefficients were not used since the solubility of HLVOCs in tissue neutral lipids and blood neutral lipids is considered to be the same. The NLE-based physiological pharmacokinetic model was then used to simulate the uptake and disposition kinetics of alpha-pinene, d-limonene, and 1,2,4-trimethylbenzene in humans. The NLE-based model developed in this study represents a novel tool for simulating the lipid concentrations and pharmacokinetics of HLVOCs without the use of tissue:blood partition coefficients.

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“…Verfeinerungen dieses physiologischen Basismodells ermöglichen die Modellierung des Einflusses der Anäs-thetikakonzentration auf das Herzzeitvolumen und auf den Kompartimentblutfluss, den Einfluss von peripheren Shunts [75] und Ventilations-Perfusions-Missverhältnissen [76]. Ein Basismodell für die Aufnahme und die Verteilung eines volatilen Anästhetikums unterteilt den Kör-per und den "closed anesthetic circuit" in ein System mit verschiedenen Kompartimenten.…”

Section: Introductionunclassified

Pharmakokinetische/pharmakodynamische Modelle für Inhalationsanästhetika

et al. 2007

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Pharmacokinetic models can be differentiated into two groups: physiological-based models and empirical models. Traditionally the pharmacokinetics of volatile anaesthetics are described using physiological-based models together with the respective tissue-blood distribution coefficients. The compartments of the empirical model have no anatomical equivalents and are merely the product of the mathematical procedure for parameter estimation. The end expiratory concentration of volatile anaesthetics is approximately equal to the arterial concentration and, therefore, the description of the transition between plasma and effect site for volatile anaesthetics plays a central role. The most important parameter here is the k(e0) value which is a time constant and describes the time delay for the transition from the central compartment to the calculated effect compartment. The k(e0) values for sevoflurane and isoflurane are the same but the concentration balance between the end-tidal concentration and the effect compartment occurs twice as quickly with desflurane. In clinical practice volatile anaesthetics are normally combined with N(2)O and/or opioids. This results in an additive interaction between volatile anaesthetics and N(2)O but a synergistic interaction of volatile anaesthetics with opioids. However, there are relatively few investigations on the interactions between the clinically widely used combination of volatile anaesthetics, N(2)O and opioids.

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PKQuest: volatile solutes – application to enflurane, nitrous oxide, halothane, methoxyflurane and toluene pharmacokinetics

Cited by 17 publications

References 71 publications

Human physiologically based pharmacokinetic model for propofol

Human physiologically based pharmacokinetic model for propofol

A Physiological Pharmacokinetic Model Based on Tissue Lipid Content for Simulating Inhalation Pharmacokinetics of Highly Lipophilic Volatile Organic Chemicals

Pharmakokinetische/pharmakodynamische Modelle für Inhalationsanästhetika

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