Halothane Biotransformation in Obese and Nonobese Patients

Bentley, John B.; Vaughan, R. W.; Gandolfi, Jay; Cork, Randall C.

doi:10.1097/00132586-198306000-00004

Cited by 9 publications

(18 citation statements)

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“…Mean serum trifluoroacetic acid concentrations and mean urine trifluoroacetic acid excretion rates in volunteers at 24 h, 4 days, and 6 days after exposure to desflurane were significantly elevated, with a peak mean serum concentration of 0.38 pmoYL at 24 h. This serum trifluoroacetic acid concentration after desflurane anesthesia is approximately 1000-fold lower than the concentration of about 500 pmoYL achieved after the administration of 0.44%-1.57% end-expired halothane for 2 h to patients having intraabdominal surgery (20). Comparison with isoflurane is difficult because only limited data are available for trifluoroacetic acid production after isoflurane administration to patients.…”

Section: Discussionmentioning

confidence: 72%

Fluoride Metabolites After Prolonged Exposure of Volunteers and Patients to Desflurane

Sutton

Koblin

Gruenke

et al. 1991

Anesthesia & Analgesia

106

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We examined the metabolism of desflurane in 13 healthy volunteers given 7.35 +/- 0.81 MAC-hours (mean +/- SD) of desflurane and 26 surgical patients given 3.08 +/- 1.84 MAC-hours (mean +/- SD). Markers of desflurane metabolism included fluoride ion measured via an ion-specific electrode, nonvolatile organic fluoride measured after sodium fusion of urine samples, and trifluoroacetic acid determined by a gas chromatographic-mass spectrometric method. In both volunteer and patient groups, postanesthesia serum fluoride ion concentrations did not differ from background fluoride ion concentrations. Similarly, postanesthesia urinary excretion of fluoride ion and organic fluoride in volunteers was comparable to preanesthesia excretion rates. However, small but significant levels of trifluoroacetic acid were found in both serum and urine from volunteers after exposure to desflurane. A peak serum concentration of 0.38 +/- 0.17 mumol/L of trifluoroacetic acid and a peak urinary excretion rate of 0.169 +/- 0.107 mumol/h were detected in volunteers at 24 h after desflurane exposure. Although these increases in trifluoroacetic acid after exposure to desflurane were statistically significant, they are approximately 10-fold less than levels seen after exposure to isoflurane. Thus, desflurane strongly resists biodegradation, but a small amount is metabolized in humans.

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Section: Discussionmentioning

confidence: 72%

Fluoride Metabolites After Prolonged Exposure of Volunteers and Patients to Desflurane

Sutton

Koblin

Gruenke

et al. 1991

Anesthesia & Analgesia

106

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“…Bentley reported higher rates of biotransformation of the CYP2E1 substrate, halothane, in obese individuals compared to those of normal weight. 3 O'Shea et al 21 also reported increased CYP2E1-dependent biotransformation toward chlorzoxasone in obese individuals. Gender-dependent differences in CYP450 activities in rodents have been known for some time.…”

Section: Discussionmentioning

confidence: 95%

“…These studies have shown increased susceptibility or increased protection to xenobiotic induced target organ toxicity. 2,3 However, limited information is available on the effect of age and gender on xenobiotic drug metabolizing enzymes in the genetically obese obaob mouse.…”

Section: Introductionmentioning

confidence: 99%

Characterization of cytochrome P450 and glutathione S-transferase activity and expression in male and female ob/ob mice

et al. 1999

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OBJECTIVE: To characterize the effect(s) of gender, age (glycemic status) and obese state, on hepatic biotransformation activities, expression of cytochrome P450 (CYP450) mRNAs and glutathione transferase activity in the obaob mouse. DESIGN: Male and female, obaob or oba mice were killed at 3 ± 4 months or 7 ± 8 months of age. Hepatic microsomes, cytosol and RNA were prepared from each animal. ANIMALS: Male and female obaob and oba mice, 3 ± 4 or 7 ± 8 months of age. MEASUREMENTS: CYP450 form-speci®c activities of CYP1A1a1A2, CYP3A and CYP2B were estimated by determining the 0-dealkylation of alkoxyresoru®n substrates (ethoxy-EROD, benzoxy-BROD and pentoxy-resoru®n, PROD, respectively). CYP2E1-dependent, 4-nitrophenol hydroxylase (PNP-OH) and CYP3A-dependent erythromycin N-demethylase (ERY-DM) were also measured in hepatic microsomes. CYP1A2, CYP2E1 and CYP3A protein in microsomal fractions was determined by ELISA. Glutathione transferase activity (GST) was determined in hepatic cytosol and CYP1A2 and CYP2E1 mRNA was estimated by Northern blot analysis. RESULTS: Female mice, regardless of glycemic status, showed an obesity enhanced level of CYP2E1-dependent PNP-OH activity and CYP2EI protein as shown by ELISA. These increases were observed to be independent of the diabetic state, since 7 ± 8 month-old mice had blood glucose levels identical to lean mice. The mRNA level of CYP2E1 in female mice also exhibited age-and obesity-in¯uenced decreases in expression. No signi®cant differences in CYP2E1 activity or expression were observed in male mice. CYP3A-dependent ERY-DM activity was signi®cantly higher in young males, regardless of phenotype. CYP3A and CYP2B activities did not differ among any animals; however, CYP1A activity, while depressed in obese animals of both genders, was signi®cantly different in old animals. Glutathione Stransferase activity was lower in obese male mice, whereas no difference was observed between lean and obese females CONCLUSION: This study supports earlier observations in man and rats that the obese state produces alterations in the expression of important oxidation and conjugation pathways. In addition, this report more thoroughly examines the role of gender and glycemic status on biotransformation activities in the obaob mouse as demonstrated by increased CYP2E1 protein and CYP2E1-dependent activity in obese females, decreased CYP1A2 protein and CYP1A2-dependent activity in obese animals, and obesity had no effect of glutathione transferase in female mice, in contrast with the previously reported obesity-dependent decrease of this activity in male mice.

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“…Evidence of liver damage may vary from moderate increases in hepatic enzymes to fulminant hepatic failure, especially in humans 1 . Several studies have indicated that concurrent hypoxia, prior induction of hepatic enzymes and prolonged arterial hypotension may increase the likelihood of hepatic injury after anaesthesia 6–9 . Other factors, including genetic susceptibility, repeated exposure to halothane, presurgical fasting and obesity, have been associated with an increased incidence of halothane‐induced hepatic necrosis 1 .…”

Section: Introductionmentioning

confidence: 99%

“…Inorganic fluoride is a common metabolite of halogenated inhalation anaesthetics. The degradation of methoxyflurane, 6,10 halothane, 6–9,11 enflurane, 11,12 isoflurane 13 and sevoflurane 14 has been associated with transient postanaesthetic increases in serum fluoride levels in mice, rats, guinea‐pigs, dogs and humans. Because trifluoroethane and difluoroethylene are volatile and are eliminated by expiration, serum fluoride is a more reliable indicator of the degree of the reductive metabolism of halothane.…”

Section: Introductionmentioning

confidence: 99%

Effects of Tail Fat on Halothane Biotransformation in Fat‐tailed Sheep

Sharifi

Vesal

2005

Clin Exp Pharma Physio

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1. The aim of the present study was to evaluate the effects of tail fat on halothane biotransformation following similar anaesthetic exposure in intact sheep and sheep with a ligated median sacral artery. 2. A prospective randomized experimental study was performed using 12 healthy, 10-12-month-old female sheep. 3. Sheep were randomly divided into two groups of six animals each and were anaesthetized twice at 2 weekly intervals. After mask induction with halothane in 100% oxygen, sheep were intubated and anaesthesia was maintained for 3 h using a rebreathing system. Serum fluoride concentration (SFC) was measured at 0, 1, 3, 6, 12, 24, 48 and 72 h following the induction of anaesthesia. Serum biochemistry was also evaluated at baseline and 72 h after anaesthesia. Induction and extubation times and time to sternal recumbency were also recorded during anaesthetic induction and recovery. Prior to the second anaesthesia (2 weeks later), the median sacral artery (MSA) was ligated under epidural anaesthesia in the experimental group. Sheep in the control group underwent sham operation. All sheep were anaesthetized as before. 4. Following the first halothane anaesthesia, SFC was significantly increased from 3 to 48 h compared with baseline. In the second stage of the experiment, the increases in SFC in the control group were similar to those seen in the first stage of the experiment. However, in MSA-ligated sheep, the increases in SFC were only significant between 3 and 12 h compared with baseline. The SFC was significantly higher in intact sheep from 3 to 72 h compared with the MSA-ligated group. Extubation and sternal recumbency times were significantly longer in intact sheep. 5. Ligation of the MSA in fat-tailed sheep induced a significant reduction in SFC, suggesting that the presence of tail fat substantially affects halothane metabolism during the peri-anaesthetic period in sheep. The greater extent of halothane biotransformation may be clinically important in, otherwise normal, obese patients.

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Halothane Biotransformation in Obese and Nonobese Patients

Cited by 9 publications

References 0 publications

Fluoride Metabolites After Prolonged Exposure of Volunteers and Patients to Desflurane

Fluoride Metabolites After Prolonged Exposure of Volunteers and Patients to Desflurane

Characterization of cytochrome P450 and glutathione S-transferase activity and expression in male and female ob/ob mice

Effects of Tail Fat on Halothane Biotransformation in Fat‐tailed Sheep

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