Metabolism of Halothane in Obese Fischer 344 Rats

Js, Biermann; Sa, Rice; Kj, Fish; Mt, Serra

doi:10.1097/00000542-198909000-00020

Cited by 4 publications

(3 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Halothane is perhaps best avoided since the combination of hypoxia and halothane may rarely be associated with hepatitis (81). Adult obese patients receiving volatile anaesthetics exhibit higher serum anaesthetic metabolite concentrations than do normal‐weight patients, and thus might be at greater risk of hepatotoxicity because of higher concentrations of reactive intermediates from halothane metabolism (99,100). However, halothane hepatitis has a disproportionately low incidence in children (101).…”

Section: Anaesthetic Managementmentioning

confidence: 99%

Childhood obesity: a challenge for the anaesthetist?

Smith

Meldrum

Brennan

2002

Pediatric Anesthesia

View full text Add to dashboard Cite

The definition of childhood obesity has not been standardized in the past, making studies difficult to compare. In spite of this, the increase in the incidence of childhood obesity is evident and has now reached epidemic proportions. Obese children experience few of the medical complications seen in obese adults. Respiratory physiology appears to be most affected, the degree of which is determined by the level of obesity. Although there is a considerable amount of information on the anaesthetic management of the obese adult, very little has been written concerning the obese child. There is less pathology in the obese child when compared with the adult but some evidence shows a higher likelihood of a critical incident occurring when anaesthetizing such children. This shows that we need to be as worried about anaesthetizing the obese child as we are for the obese adult. This concern should increase with increasing body mass index.

show abstract

Section: Anaesthetic Managementmentioning

confidence: 99%

Childhood obesity: a challenge for the anaesthetist?

Smith

Meldrum

Brennan

2002

Pediatric Anesthesia

View full text Add to dashboard Cite

show abstract

“…Subsequent hydrolysis to yield trifluoroacetic acid (TFA) is a major pathway but minor amounts of trifluoroacetyl-protein adducts or CF 3 CO-proteins may also be formed (Harris et al, 1991;Huwyler et al, 1992). TFA has been demonstrated as a urinary metabolite of rats exposed to both HCFC-123 (Harris et al, 1991;Vinegar etal., 1994;Loizou et al, 1994) and halothane (Harris et al, 1991;Eckes and Buch, 1985;Biermann et al, 1989). Furthermore, exposure of rats to a single dose of HCFC-123 resulted in the formation of CF 3 CO-proteins that were immunochemically identical to those obtained with a single dose of halothane as a substrate (Huwyler et al, 1992).…”

mentioning

confidence: 94%

“…Because of the historical use of halothane as an anesthetic, the kinetics of halothane have been studied extensively in humans (Torn et al, 1972;Yasuda et al, 1991;Cahalan et al, 1981;Carpenter et al, 1986;Bentley etal., 1982;Rehder et al, 1967) and rodents (Stern et al, 1990;Eckes and Buch, 1985;Biermann et al, 1989;Gargas and Andersen, 1982;Andersen et al, 1980). While recent laboratory studies on the kinetics of HCFC-123 in rats have been published (Vinegar et al, 1994;Loizou et al, 1994), HCFC-123 is a compound that does not have a historical commercial use and human exposure data are not available.…”

mentioning

confidence: 99%

Rat to Human Extrapolation of HCFC-123 Kinetics Deduced from Halothane Kinetics: A Corollary Approach to Physiologically Based Pharmacokinetic Modeling

WILLIAMS¹,

VINEGAR²,

MCDOUGAL³

et al. 1996

Toxicol Sci

View full text Add to dashboard Cite

The goal of this study was to develop a human physiologically based pharmacokinetic (PBPK) model for the chemical HCFC-123 (2,2-dichloro-l,l,l-trifluoroethane) and its major metabolite, trifluoroacetic acid (TFA). No human kinetic data for HCFC-123 are available, thus a corollary approach was developed. HCFC-123 is a structural analog of the common anesthetic agent halothane (2-bromo-2-chloro-l,l,l-trifluoroethane) and follows a common pathway of oxidative biotransformation, resulting in the formation of the same metabolite, TFA. In this study, halothane models for rats and humans were developed and validated. Then the corollary approach was used to develop a human HCFC-123 model from a rat HCFC-123 model. This strategy was implemented by using a previously validated PBPK model for HCFC-123/TFA in the Fischer 344 rat as a template model for halothane in rats. Model predictions were then compared to, and were in good agreement with, measured values for the concentration of halothane in rat blood and fat tissue. A human PBPK model for halothane was developed. The identical model structure (with the exception of the description for the fat compartment) that was used to describe halothane and TFA in the rat was used for describing halothane and TFA in the human. Human physiological parameters for tissue volumes and flows were taken from the literature, and human tissue partition coefficients for halothane were measured in the laboratory. Based on reported similarity in metabolism of halothane by humans and rats, metabolic constants for halothane in the rat were used in the human model, and specific parameters describing the kinetics of TFA were estimated by optimization. The model was validated against human exposure data for halothane from six published studies (expired breath concentrations of halothane and serum/urine data for TFA). A similar approach was then used to derive a human HCFC-123 model for humans from the HCFC-123 rat model. The corollary approach described here illustrates the innovative use of template model ' To whom correspondence should be addressed. structures to aid in the development and validation of models for structural analogs with similar metabolism and activity in biologic systems. Furthermore, given that the PBPK model adequately describes the kinetics of halothane in rats and humans and of HCFC-123 in rats, use of the human PBPK model is proposed for deriving dose-response estimates of human health risks in the absence of human kinetic data, c IWS society of Toricofcpgjr

show abstract