Physiologically based pharmacokinetic modeling of arterial – antecubital vein concentration difference

Levitt, David G.

doi:10.1186/1472-6904-4-2

Cited by 26 publications

(32 citation statements)

References 53 publications

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“…The average concentration of ketamine in plasma was at a low, subanesthetic level of 164 ng/ml (SD 34) at the end of the PET scan. The lower drug concentrations measured at the start of the PET scan may be in part explained by incomplete mixing of the drug in the entire circulating blood volume (Levitt, ). As ketamine is also suspected to release other brain monoamines in addition to NA, we used a striatal dopamine D2 receptor binding study as reference for the targeted ketamine concentration.…”

Section: Discussionmentioning

confidence: 99%

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

Lehto

Hirvonen²,

Johansson

et al. 2015

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This study explored the use of the α2C -adrenoceptor PET tracer [(11) C]ORM-13070 to monitor α2C -AR occupancy in the human brain. The subtype-nonselective α2 -AR antagonist atipamezole was administered to eight healthy volunteer subjects to determine its efficacy and potency (Emax and EC50 ) at inhibiting tracer uptake. We also explored whether the tracer could reveal changes in the synaptic concentrations of endogenous noradrenaline in the brain, in response to several pharmacological and sensory challenge conditions. We assessed occupancy from the bound-to-free ratio measured during 5-30 min post injection. Based on extrapolation of one-site binding, the maximal extent of inhibition of striatal [(11) C]ORM-13070 uptake (Emax ) achievable by atipamezole was 78% (95% CI 69-87%) in the caudate nucleus and 65% (53-77%) in the putamen. The EC50 estimates of atipamezole (1.6 and 2.5 ng/ml, respectively) were in agreement with the drug's affinity to α2C -ARs. These findings represent clear support for the use of [(11) C]ORM-13070 for monitoring drug occupancy of α2C -ARs in the living human brain. Three of the employed noradrenaline challenges were associated with small, approximately 10-16% average reductions in tracer uptake in the dorsal striatum (atomoxetine, ketamine, and the cold pressor test; P < 0.05 for all), but insulin-induced hypoglycemia did not affect tracer uptake. The tracer is suitable for studying central nervous system receptor occupancy by α2C -AR ligands in human subjects. [(11) C]ORM-13070 also holds potential as a tool for in vivo monitoring of synaptic concentrations of noradrenaline, but this remains to be further evaluated in future studies.

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Section: Discussionmentioning

confidence: 99%

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

Lehto

Hirvonen²,

Johansson

et al. 2015

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“…The model parameters (organ blood flow, volume, etc.) are identical to those used in previous applications of PKQuest [3-9]. The connective tissue is divided between two organs: "tendon" with a relatively low blood flow, and "other" with a higher blood flow [8].…”

Section: Methodsmentioning

confidence: 99%

“…The model describes the pharmacokinetics in terms of realistic human parameters, such as the organ blood flow and the tissue/blood partition. The PBPK model is implemented in PKQuest, a new software routine that has now been applied to more than 25 different solutes with a wide range of pharmacokinetic properties [3-9]. …”

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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“…The antecubital vein drains blood from the hand and the superficial layers of the forearm. The concentration of solute in the antecubital vein is different from the concentrations of solute in the arterial and central venous blood (Levitt 2004). However, the blood in the antecubital vein is in rapid equilibrium with arterial and central venous blood relative to the fat and other tissue compartments.…”

Section: Methodsmentioning

confidence: 99%

PBTK Modeling Demonstrates Contribution of Dermal and Inhalation Exposure Components to End-Exhaled Breath Concentrations of Naphthalene

Kim

Andersen

Chao

et al. 2007

Environ Health Perspect

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BackgroundDermal and inhalation exposure to jet propulsion fuel 8 (JP-8) have been measured in a few occupational exposure studies. However, a quantitative understanding of the relationship between external exposures and end-exhaled air concentrations has not been described for occupational and environmental exposure scenarios.ObjectiveOur goal was to construct a physiologically based toxicokinetic (PBTK) model that quantitatively describes the relative contribution of dermal and inhalation exposures to the end-exhaled air concentrations of naphthalene among U.S. Air Force personnel.MethodsThe PBTK model comprised five compartments representing the stratum corneum, viable epidermis, blood, fat, and other tissues. The parameters were optimized using exclusively human exposure and biological monitoring data.ResultsThe optimized values of parameters for naphthalene were a) permeability coefficient for the stratum corneum 6.8 × 10−5 cm/hr, b) permeability coefficient for the viable epidermis 3.0 × 10−3 cm/hr, c) fat:blood partition coefficient 25.6, and d) other tissue:blood partition coefficient 5.2. The skin permeability coefficient was comparable to the values estimated from in vitro studies. Based on simulations of workers’ exposures to JP-8 during aircraft fuel-cell maintenance operations, the median relative contribution of dermal exposure to the end-exhaled breath concentration of naphthalene was 4% (10th percentile 1% and 90th percentile 11%).ConclusionsPBTK modeling allowed contributions of the end-exhaled air concentration of naphthalene to be partitioned between dermal and inhalation routes of exposure. Further study of inter- and intraindividual variations in exposure assessment is required to better characterize the toxicokinetic behavior of JP-8 components after occupational and/or environmental exposures.

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Physiologically based pharmacokinetic modeling of arterial – antecubital vein concentration difference

Cited by 26 publications

References 53 publications

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

Human physiologically based pharmacokinetic model for propofol

PBTK Modeling Demonstrates Contribution of Dermal and Inhalation Exposure Components to End-Exhaled Breath Concentrations of Naphthalene

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Physiologically based pharmacokinetic modeling of arterial – antecubital vein concentration difference

Cited by 26 publications

References 53 publications

Validation of [11C]ORM‐13070 as a PET tracer for alpha2c‐adrenoceptors in the human brain

Validation of [11C]ORM‐13070 as a PET tracer for alpha2c‐adrenoceptors in the human brain

Human physiologically based pharmacokinetic model for propofol

PBTK Modeling Demonstrates Contribution of Dermal and Inhalation Exposure Components to End-Exhaled Breath Concentrations of Naphthalene

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Product

Resources

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Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain

Validation of [¹¹C]ORM‐13070 as a PET tracer for alpha_2c‐adrenoceptors in the human brain