Serum protein binding of propofol in patients with renal failure or hepatic cirrhosis

Costela, J L; Jiménez, Rosa M.; Calvo, Rosario; Súárez, Eduardo Viñuela; Carlos, R.

doi:10.1111/j.1399-6576.1996.tb04521.x

Cited by 50 publications

(34 citation statements)

References 18 publications

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“…Experimental measurements of the normal human free plasma propofol fraction (freepl) fall into two different ranges. The smaller value of about 0.01 comes from a series of publications by Suarez and colleagues using ultrafiltration [14-16]. A larger value of about 0.02 has been reported by several other research groups: Using equilibrium dialysis, Altmayer et.…”

Section: Methodsmentioning

confidence: 96%

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: Methodsmentioning

confidence: 96%

Human physiologically based pharmacokinetic model for propofol

Levitt

Schnider

2005

BMC Anesthesiol

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“…31–34 The dose of propofol used clinically in children varies widely but typically ranges from about 1–10 μg/mL (blood concentration) with higher doses used for induction of anesthesia and lower doses used for maintenance. 35–37 In addition, cell culture and whole animal studies have shown that propofol can induce toxicity at high doses or prolonged exposure times after a single exposure.…”

Section: Methodsmentioning

confidence: 99%

Down-regulation of MicroRNA-21 Is Involved in the Propofol-induced Neurotoxicity Observed in Human Stem Cell–derived Neurons

Twaroski

Yan²,

Olson³

et al. 2014

Anesthesiology

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Background Recent studies in various animal models have suggested that anesthetics such as propofol, when administered early in life, can lead to neurotoxicity. These studies have raised significant safety concerns regarding the use of anesthetics in the pediatric population and highlight the need for a better model by which to study anesthetic-induced neurotoxicity in humans. Human embryonic stem cells (hESCs) are capable of differentiating into any cell type and represent a promising model to study mechanisms governing anesthetic-induced neurotoxicity. Methods Cell death in hESC-derived neurons was assessed using TUNEL staining and microRNA (miR) expression was assessed using quantitative reverse transcription polymerase chain reaction (qRTPCR). miR-21 was overexpressed and knocked down using a miR-21 mimic and antagomir, respectively. Sprouty 2 was knocked down using a small interfering RNA and the expression of the miR-21 targets of interest was assessed by Western blot. Results Propofol dose and exposure time-dependently induced significant cell death (n = 3) in the neurons and downregulated several microRNAs, including miR-21. Overexpression of miR-21 and knockdown of Sprouty 2 attenuated the increase in TUNEL-positive cells following propofol exposure. In addition, miR-21 knockdown increased the number of TUNEL-positive cells by 30% (n = 5). Finally, activated Signal Transducer and Activator of Transcription 3 (STAT3) and protein kinase B (Akt) were downregulated and Sprouty 2 was upregulated following propofol exposure (n = 3). Conclusions These data suggest that: (1) hESC-derived neurons represent a promising in vitro human model for studying anesthetic-induced neurotoxicity, (2) propofol induces cell death in hESC-derived neurons and (3) the propofol-induced cell death may occur via a STAT3/miR-21/Sprouty2-dependent mechanism.

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“…Until now, there have been only a few studies on the pharmacokinetics and safety of sedation in patients with end-stage liver disease [2][3][4][5][6][7][8][9][10]. Midazolam may precipitate overt hepatic encephalopathy (OHE) or minimal hepatic encephalopathy (MHE), but cases of OHE requiring intervention after an endoscopic procedure are unusual in clinical practice.…”

Section: Introductionmentioning

confidence: 99%