Metabolism Of Isoflurane Research Articles

Polymorphic Drug Metabolism in Anaesthesia

A substantial part of the interindividual variability in response to drugs and xenobiotics is related to genetically-determined impairment in drug metabolism. Several drug-metabolising enzymes are polymorphic in humans and often polymorphisms are strongly related to altered drug biodisposition and to the risk of developing adverse effects. Drugs used in general anaesthesia undergo polymorphic metabolism. Among these, halothane is metabolized by cytochrome P450 (CYP) 2E1 and, to a lesser extent, by CYP3A4 and CYP2A6. CYP2E1 also plays a key role in the metabolism of isoflurane, sevoflurane, enflurane and desflurane. CYP2B6, CYP3A4 and CYP2C9 play a relevant role in the metabolism of ketamine. The enzymes involved in the metabolism of thiopental and etomidate remains to be elucidated. Propofol is metabolized mainly by glucuronidation by uridine diphosphate-glucuronosyltransferases (UGTs) and by hydroxylation by CYP2B6 and CYP2C enzymes. The enzymes SULT1A1 and NQO1 participate in later steps in propofol metabolism. All the above-mentioned anaesthetic-metabolising enzymes are polymorphic in man. The present review analyzes the importance of enzymes in the metabolism of anaesthetics and common polymorphisms related to the biotransformation of general anaesthetics and it raises hypotheses on genetic and non-genetics factors related to altered response to anaesthetics that require further investigation. Based on functional relevance and allele frequencies, we identify the most promising targets for the clinical use of pharmacogenomic techniques in anaesthesia to prevent altered pharmacokinetics or adverse drug effects.

Plasma Fluoride Concentrations During and After Prolonged Anesthesia

Serum inorganic fluoride concentrations were studied in 19 adult patients undergoing prolonged head and neck surgery with either halothane or isoflurane anesthesia (mean 19.5 and 19.2 MAC-hours, respectively). In the group of nine patients anesthetized with isoflurane, plasma inorganic fluoride increased from a mean concentration of 3.5 mumols/L (baseline) to a peak of 43.2 mumols/L. Forty percent of the patients in the isoflurane group had peak plasma inorganic fluoride concentrations of more than 50 mumol/L. In the group that received halothane, plasma inorganic fluoride concentrations increased from a mean of 3.8 mumols/L to a peak of 12.6 mumols/L. Despite similar exposures to both anesthetics, the differences in serum inorganic fluoride concentrations between the two groups were significant at 10, 24, and 48 h after induction of anesthesia (P = 0.035, P = 0.003, and P = 0.003, respectively). Serum electrolyte, urea, and creatinine concentrations and urine output rates during and after surgery were similar in both groups. We conclude that, after anesthesia of up to 20 MAC-hours, metabolism of isoflurane to inorganic fluoride may be of a greater magnitude than has previously been realized. Although no clinical or biochemical evidence was found to suggest postoperative renal dysfunction, we recommend caution using isoflurane when prolonged anesthesia and surgery are planned.

Metabolism of desflurane and isoflurane to fluoride ion in surgical patients

The metabolism of isoflurane and the investigational volatile anaesthetic desflurane to fluoride ion was examined in 25 surgical patients. The patients were randomly assigned to four groups, to receive isoflurane or desflurane at either 0.65 MAC or 1.25 MAC. Anaesthesia was induced in all patients with thiopentone and midazolam and included nitrous oxide 60% in addition to the volatile agent. Blood was drawn before induction and at the end of the operation for determination of serum fluoride ion concentration. Plasma fluoride ion concentrations increased (+ 1.36 +/- 0.93 microM, P less than 0.01) in patients receiving isoflurane but were unchanged (-0.13 +/- 0.50 microM) in patients receiving desflurane. Metabolic release of fluoride ion is less with desflurane than with isoflurane during administration of the anaesthetics to surgical patients, and is unlikely to be of clinical significance.

Metabolism of Isoflurane in Patients Receiving Isoniazid

Metabolism of Isoflurane in Patients Receiving Isoniazid

Metabolism of Isoflurane in Patients Receiving Isoniazid

Gauntlett, Ian S. FFARCS; Koblin, Donald D. MD, PhD; Fahey, Mark R. MD; Konopka, Krystyna MD, PhD; Gruenke, Larry D. PhD; Waskell, Lucy MD, PhD; Eger, Edmond I. II MD Author Information

Hepatotoxicity and Metabolism of Isoflurane in Rats with Cirrhosis

A rat model was used to determine whether isoflurane exacerbates liver dysfunction and whether its metabolism is changed in the presence of cirrhosis. Male Wistar rats were gavaged weekly with carbon tetrachloride until cirrhosis was well advanced. They and control rats without pretreatment with carbon tetrachloride and without cirrhosis were then exposed to 1.45% (1 MAC) isoflurane for 3 hours. Blood and urine samples were taken before, immediately, as well as 4, 24, 48, and 72 hours after anesthesia to measure liver function and isoflurane defluorination. After the last samples had been obtained, the rats were sacrificed and the liver removed for histologic examination and in vitro metabolic studies. Serum levels of SGOT and SGPT and inorganic fluoride production in rats with cirrhosis were similar to those in control rats without cirrhosis. Concentrations of cytochromes b5 and p-450 and specific activities of microsomal defluorinase and several cytosolic enzymes were significantly lower in cirrhotic than in noncirrhotic liver, but their total amounts in whole liver were the same. The results imply that cirrhosis does not increase the risk of acute hepatotoxicity of isoflurane. They also demonstrate that metabolism of isoflurane and perhaps other volatile anesthetics may be unaffected in rats with cirrhosis, even though liver architecture is severely disrupted.

Effect of streptozotocin-induced diabetes in the rat on the metabolism of fluorinated volatile anesthetics.

Three weeks after dosing male Fischer 344 rats with streptozotocin to induce diabetes, enflurane was administered ip, and 1 h later, fluoride levels were measured in plasma and livers were removed. Hepatic microsomes were prepared, and the oxidative defluorination of enflurane, isoflurane, and methoxyflurane and the reductive defluorination of halothane were measured in vitro. In diabetic rats the defluorination of enflurane was increased 3.4-fold over control levels in vivo and 2.7-fold in vitro. Insulin treatment prevented these effects. In vitro metabolism of isoflurane by livers from diabetic rats was 2.5-fold greater than by livers from control rats, but defluorination of methoxyflurane and of halothane was not altered. The results show that streptozotocin-induced diabetes in rats enhances the defluorination of enflurane and of isoflurane but not of methoxyflurane or halothane.

Isoflurane

Isoflurane is metabolized by both rat and human hepatic microsomal cytochrome P-450 in vitro to fluoride ion and organofluorine metabolites. The forms of rat liver microsomal cytochrome P-450 induced by phenobarbital and pregnenolone-16 alpha-carbonitrile appear to be involved in the metabolism of isoflurane, while the forms induced by beta-naphthoflavone do not. Different pathways are favored for the metabolism of isoflurane by rat and by human liver microsomes: trifluoroacetaldehyde appears to be produced from isoflurane by rat liver microsomal cytochrome P-450, while trifluoroacetate or other nonvolatile fluorinated metabolites were not. The trifluoroacetaldehyde so produced binds tightly to microsomal constituents. Human liver microsomes converted isoflurane extensively to nonvolatile fluorinated products, one of which appears to be trifluoroacetate. The proposed pathways for the metabolism of isoflurane are considered in view of the above results.

Renal effects and metabolism of isoflurane in man.

The intra- and postanesthetic renal effects and metabolism of isoflurane were studied in nine surgical patients; six control patients received halothane. Isoflurane was metabolized to a slight extent, with a mean peak serum inorganic fluoride concentration of 4.4 ± 0.4 µM/l, measured six hours after