Effects of hypothermia on the elimination of ethanol, diazepam and oxazepam in rat liver slice incubations

Abstract

The elimination of ethanol, diazepam and oxazepam which are metabolised by different enzymes, has been studied for 30, 60, 90 and 120 min at 37, 27, 17 and 7 degrees C in rat liver slice incubations. Ethanol elimination followed zero-order kinetics at all temperatures, while the benzodiazepines consistently displayed first-order kinetics. No sign of phase transition was observed in the respective Arrhenius-plots. Ethanol elimination was more temperature dependent than the elimination of diazepam, while the elimination of oxazepam was little influenced by temperature. This is shown by the temperature ratios (Q10) and energies of activation (Ea) of 1.76, 1.56, 1.24 and 40.5, 31.9, 15.2 for ethanol, diazepam and oxazepam, respectively. This means that ethanol, diazepam and oxazepam elimination was reduced by 25, 22 and 14%, respectively, for each 10 degrees C of temperature reduction, which is considerably lower than the commonly observed 50% reduction of enzyme activity. We conclude that observations made for one drug on temperature dependent elimination may not apply to other drugs.

An In Vitro Model of Human Acute Ethanol Exposure That Incorporates CXCR3- and CXCR4-Dependent Recruitment of Immune Cells

“…Our culture system is based upon incubation of slices in wells or on tissue culture insert supports for up to 48 h. Morphological evidence and functional albumin secretion, MTT reduction, and glucose uptake, as well as responses to ethanol and cytokine treatment, confirm that viability is maintained for this period. This extends the duration of much reported evidence using rodent slices for toxicological and metabolic studies, where culture durations of a few hours are not uncommon (Mortensen and Dale, 1995;Naik et al, 2004) and where visual assessment of tissue integrity is not always performed. However, we acknowledge that between 24 and 48 h, we began to observe central necrosis of slices both in wells and on supports with decreased nuclear integrity and loss of morphological structure compared with the periphery of the section that maintained adequate media perfusion and gaseous exchange.…”

Effects of Hypothermia on the Disposition of Morphine, Midazolam, Fentanyl, and Propofol in Intensive Care Unit Patients

“…Reduced metabolism due to changes in enzyme activity during hypothermia may increase drug serum levels, and thus drug effects and duration of action (Polderman, 2004;Arpino and Greer, 2008). However, the effects of hypothermia on the activity of different enzymes vary; whereas 10°C lower temperature reduced cytochrome P450 (P450) activity on diazepam by 22%, conjugation of oxazepam was reduced by only 14% (Mortensen and Dale, 1995). In addition, whereas CYP3A and CYP2E activity as measured by clearance of midazolam and chlorzoxazone was approximately 50 and 60% lower in rats given cardiac arrest and TH compared with the control group, no differences were demonstrated for CYP2C/D .…”

“…In addition, whereas CYP3A and CYP2E activity as measured by clearance of midazolam and chlorzoxazone was approximately 50 and 60% lower in rats given cardiac arrest and TH compared with the control group, no differences were demonstrated for CYP2C/D . This substrate specificity implies that the effects of hypothermia on pharmacokinetics (PK) may vary between drugs (Mortensen and Dale, 1995;.…”

Influence du site de prélèvement sur l’étude cinétique et métabolique de l’éthanol

“…Toutes ces modifications contribuent à une réduction du volume intravasculaire de distribution [51]. Enfin, pour Mortensen et Dale qui ont travaillé directement sur le tissu hépatique, la température a une influence directe sur plusieurs systèmes enzymatiques dont l'alcool déshydrogénase [52]. Si les autres auteurs ne l'ont jamais tout à fait exclu, la part relative de cet effet leur semble plus faible que celui des variations circulatoires.…”