Concentrations of lidocaine and monoethylglycine xylidide in brain, cerebrospinal fluid, and plasma during lidocaine-induced epileptiform electroencephalogram activity in rabbits: the effects of epinephrine and hypocapnia.

UNLABELLED: When injecting lidocaine into tissues, the mean toxic dose of lidocaine may be increased by adding epinephrine to lidocaine and by decreasing the PaCO(2). In contrast, when lidocaine is introduced directly into an artery or vein, adding epinephrine to lidocaine may decrease the mean toxic dose of lidocaine. Less is known about the effects of decreased PaCO(2) on intravascular lidocaine toxicity. We infused lidocaine in 24 rabbits at 4 mg. kg(-1). min(-1) with/without epinephrine and with/without hypocapnia. We measured the time to onset of lidocaine-induced seizures, total dose of lidocaine at the time of seizures, and concentrations of lidocaine and monoethylglycine xylidide (MEGX), a metabolite of lidocaine, in plasma, brain, and cerebrospinal fluid. Epinephrine decreased onset time by 11% with hypocapnia and by 21% with normocapnia, and it increased plasma MEGX by 1 microg/mL with hypocapnia and 2 microg/mL with normocapnia. Hypocapnia increased onset time by 18% without epinephrine and by 33% with epinephrine, and it increased whole-brain MEGX by 10 microg/mL without epinephrine and by 14 microg/mL with epinephrine. We conclude that, when lidocaine is given intravascularly, hypocapnia increases onset time and lidocaine dose required for seizures. These effects occur with no change in the concentration of lidocaine in plasma or the brain. IMPLICATIONS: Hypocapnia increases the toxic dose of lidocaine given IV without altering lidocaine concentrations in blood, brain, or cerebrospinal fluid. Whole-brain monoethylglycine xylidide concentration is greater during hypocapnia than during normocapnia, and the addition of epinephrine to lidocaine increases the concentration of monoethylglycine xylidide in plasma.

Endotracheal lidocaine administration via an esophageal combitube.

The purpose of this study was to test the hypothesis that lidocaine is systemically absorbed after administration via a Combitube placed in the esophagus, and that therapeutically significant plasma lidocaine concentrations can be attained using this route with standard endotracheal doses (2.0 mg/kg). During general anesthesia, 27 elective surgical patients received 2.0 mg/kg lidocaine (diluted as necessary with 0.9% saline to a minimum total volume of 10 mL) via a Combitube (study group, n = 13) or an endotracheal tube (control group, n = 14). Venous blood samples were drawn for 3 h after lidocaine administration and plasma concentrations determined by gas chromatography using a nitrogen-phosphorus detector (NPD). Overall, average lidocaine concentrations were maximal after 5 min, reaching 0.8+/-0.7 and 1.7+/-0.7 microg/mL in the Combitube and endotracheal tube groups, respectively. Individual patient peak concentrations averaged 1.0+/-0.7 and 2.2+/-1.1 microg/mL in the same two groups, 19+/-16 and 10+/-15 min after lidocaine administration, respectively. No patients reported chest discomfort or dyspnea upon awakening, and no other side effects were noted. In support of the hypothesis, administration of lidocaine via an esophageal Combitube results in systemic drug uptake; however, at conventional endotracheal doses, plasma concentrations are subtherapeutic. It remains to be determined whether higher doses of lidocaine administered via an esophageal Combitube will result in therapeutic plasma concentrations.

Menstrual cycle variability in midazolam pharmacokinetics.

Activity of cytochrome P450 3A4 (CYP3A4), the most abundant human P450 isoform and responsible for metabolizing approximately half of all therapeutic agents, has been speculated to vary during the menstrual cycle. This investigation evaluated CYP3A4 activity during the menstrual cycle, using midazolam clearance as a metabolic probe. Midazolam (1 mg i.v.) was administered to nonsmoking, nonpregnant female volunteers (N = 11, age 26 +/- 5 years) with normal menstrual cycles on three separate occasions during the same cycle: days 2 (menstrual phase), 13 (estradiol peak), and 21 (progesterone peak). Venous plasma midazolam concentrations were determined by gas chromatography-mass spectrometry. Midazolam clearance was determined by noncompartmental and compartmental analysis. Midazolam plasma disposition did not differ between phases of the menstrual cycle. There was no significant difference in any measure of midazolam clearance. Noncompartmental clearances (mean +/- SD) were 7.36 +/- 2.73, 6.34 +/- 3.59, and 6.23 +/- 2.04 ml/kg/min, respectively, on days 2, 13, and 21 of the menstrual cycle. These results suggest no difference in hepatic CYP3A4 activity on menstrual cycle days 2, 13, and 21. Consideration of menstrual cycle variability in the metabolism of CYP3A4 substrates does not appear indicated in the dosing or design of clinical trials.

Posttreatment with propofol terminates lidocaine-induced epileptiform electroencephalogram activity in rabbits: effects on cerebrospinal fluid dynamics.

UNLABELLED: There are no controlled studies to determine whether propofol given after the onset of lidocaine-induced seizures (posttreatment) stops lidocaine-induced seizures. In this study, we determined whether posttreatment with propofol abolishes lidocaine-induced epileptiform electroencephalogram (EEG) activity as effectively as does midazolam, and cerebrospinal fluid (CSF) dynamics during lidocaine-induced epileptiform EEG activity and its treatment. EEG activity and CSF dynamics were determined in two groups of anesthetized rabbits at each of four experimental conditions: baseline, lidocaine-induced epileptiform activity, treatment with midazolam (n = 6) or propofol (n = 6), and return to baseline. The analog EEG signal was converted into a set of digital parameters using aperiodic analysis, and CSF dynamics were determined using ventriculocistemal perfusion. Propofol (3.8 +/- 1.3 mg/kg) stopped epileptiform activity, as did midazolam (2.0 +/- 1.7 mg/kg). The rates of CSF formation or reabsorption and resistances to CSF reabsorption or flow at the arachnoid villi did not differ among conditions or between groups. Our results indicate that propofol and midazolam both terminate epileptiform activity without changing CSF dynamics. IMPLICATIONS: Propofol may be an alternative to benzodiazepines for treating lidocaine-induced epileptiform electroencephalogram activity in patients.

Endotracheal flumazenil: a new route of administration for benzodiazepine antagonism.

The purpose of this study was to determine if flumazenil is absorbed from broncho-pulmonary tissue after intratracheal administration and whether therapeutically significant plasma concentrations can be obtained. Six elective surgical patients received a dose of 1.0 mg flumazenil in 10 mL saline intratracheally during general anesthesia. Blood samples were drawn for 6 hours after administration and plasma concentrations were determined by gas chromatography-mass spectrometry (GC-MS). An average peak plasma flumazenil concentration of 65.9 +/- 43.1 ng/mL was attained within 1 minute after administration. No patients reported chest discomfort or dyspnea upon awakening and there were no other side effects noted. Administration of flumazenil via an endotracheal tube results in rapid attainment of therapeutic blood levels.

Acute tolerance and reversal of the motor control effects of midazolam.

The purpose of this study was to determine whether acute tolerance develops to the motor control effects of the short-acting benzodiazepine, midazolam. Using a bolus and constant infusion scheme, 40 healthy adults received a 70-min intravenous infusion of either saline (n = 20) or 6.1 (SE = 0.2) mg midazolam (n = 20). Following the 70-min infusion period, half of the subjects in each group (n = 10) received a 25-min intravenous infusion of flumazenil (benzodiazepine antagonist); the remainder of the subjects (n = 10/group) received a 25-min infusion of saline. Drug administration during both infusion periods was double blind. Prior to the infusions, subjects were trained in a motor control assessment battery. Throughout both infusions, repeated motor control testing and blood sampling were performed. The initial (10 min) midazolam plasma concentration was 52.0 (SE = 2.2) ng/ml. Plasma midazolam concentration rose gradually to 60.7 (SE = 2.1) ng/ml at the end of the infusion (70 min). Midazolam initially impaired performance on the motor control tasks. However, performance improved in subjects receiving midazolam despite the gradual increase in midazolam concentrations. This suggests that the recovery of motor task performance may be attributable to the development of acute tolerance rather than to waning drug concentrations. Flumazenil immediately reversed midazolam's effects on the visual tracking task. However, there was little evidence for precipitation of muscle force rebound, which has been hypothesized to result from the same underlying mechanism that is responsible for acute tolerance development.

Plasma levels of 2% lidocaine with 1:100,000 epinephrine with young children undergoing dental procedures.

Lidocaine levels were determined for 12 children, aged 55 to 150 mo, who received routine dental treatment, including multiple intraoral injections of 2% lidocaine (2.6 to 6.4 mg/kg) with 1:100,000 epinephrine. Peak plasma concentrations of lidocaine ranged from 0.7 to 3.8 mug/ml at 5 to 15 min postinjection. Generally accepted threshold concentrations for the onset of central nervous system toxicity are 5 to 10 mug/ml. In this study, no child approached these levels when given local anesthesia for dental procedures.

The role of cytochrome P450 3A4 in alfentanil clearance. Implications for interindividual variability in disposition and perioperative drug interactions.

BACKGROUND: There is considerable unexplained variability in alfentanil pharmacokinetics, particularly systemic clearance. Alfentanil is extensively metabolized in vivo, and thus systemic clearance depends on hepatic biotransformation. Cytochrome P450 3A4 was previously shown to be the predominant P450 isoform responsible for human liver microsomal alfentanil metabolism in vitro. This investigation tested the hypothesis that P450 3A4 is responsible for human alfentanil metabolism and clearance in vivo. METHODS: Nine healthy male volunteers who provided institutionally approved written informed consent were studied in a three-way randomized crossover design. Each subject received alfentanil (20 micrograms/kg given intravenously) 30 min after midazolam (1 mg injected intravenously) on three occasions: control; high P450 3A4 activity (rifampin induction); and low P450 3A4 activity (selective inhibition by troleandomycin). Midazolam is a validated selective in vivo probe for P450 3A4 activity. Venous blood was sampled for 24 h and plasma concentrations of midazolam and alfentanil and their primary metabolites 1'-hydroxymidazolam and noralfentanil were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were determined by two-stage analysis using both noncompartmental and three-compartment models. RESULTS: Plasma alfentanil concentration-time profiles depended significantly on P450 3A4 activity. Alfentanil noncompartmental clearance was 5.3 +/- 2.3, 14.6 +/- 3.8, and 1.1 +/- 0.5 ml.kg-1.min-1, and elimination half-life was 58 +/- 13, 35 +/- 7, and 630 +/- 374 min, respectively, in participants with normal (controls), high (rifampin), and low (troleandomycin) P450 3A4 activity (means +/- SD; P < 0.05 compared with controls). Multicompartmental modeling suggested a time-dependent inhibition-resynthesis model for troleandomycin effects on P450 3A4 activity, characterized as k10(t) = k10[1-phi e-alpha(t-tzero)], where k10(t) is the apparent time-dependent rate constant, k10 is the uninhibited rate constant, phi is the fraction of P450 3A4 inhibited, and alpha is the apparent P450 3A4 reactivation rate. Alfentanil clearance was calculated as V1 k10 for controls and men receiving rifampin, and as V1.average k10(t) for men receiving troleandomycin. This clearance was 4.9 +/- 2.1, 13.2 +/- 3.6, and 1.5 +/- 0.8 ml.kg-1.min-1, respectively, in controls and in men receiving rifampin or troleandomycin. There was a significant correlation (r = 0.97, P < 0.001) between alfentanil systemic clearance and P450 3A4 activity. CONCLUSIONS: Modulation of P450 3A4 activity by rifampin and troleandomycin significantly altered alfentanil clearance and disposition. These results strongly suggest that P450 3A4 is the major isoform of P450 responsible for clinical alfentanil metabolism and clearance. This observation, combined with the known population variability in P450 3A4 activity, provides a mechanistic explanation for the interindividual variability in alfentanil disposition. Furthermore, known susceptibility of human P450 3A4 activity to induction and inhibition provides a conceptual framework for understanding and predicting clinical alfentanil drug interactions. Finally, human liver microsomal alfentanil metabolism in vitro is confirmed as an excellent model for human alfentanil metabolism in vivo.

Pharmacokinetics of oral triazolam in children.

The purpose of this study was to determine the pharmacokinetic behavior of triazolam in children. Nine healthy children, aged 6 to 9 years, received oral triazolam (0.025 mg/kg suspended in Kool-Aid, Kraft General Foods, Chicago, IL) before dental treatment. Plasma triazolam concentrations were measured by gas chromatography/mass spectrophotometry at approximately 5, 15, 30, 45, 60, 90, 120, 180, and 240 minutes. A one-compartment model with first-order absorption and varying parameters was used, and estimated concentration curves were obtained for each subject. The observed peak plasma concentration was 8.5 +/- 3.0 ng/mL (mean +/- SD). The observed time to peak plasma concentration was 74 +/- 25 minutes. Elimination half-life was 213 +/- 144 minutes. Substantial recovery from signs and symptoms of clinical sedation required 180 to 240 minutes. The long duration of effect and relatively slow elimination should be noted by clinicians concerned with patient safety.

Intravenous lidocaine decreases but cocaine does not alter the rate of cerebrospinal fluid formation in anesthetized rabbits.

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.

Identification of the enzyme responsible for oxidative halothane metabolism: implications for prevention of halothane hepatitis.

BACKGROUND: Fulminant hepatic necrosis ("halothane hepatitis") is an unusual and often fatal complication of halothane anaesthesia. It is mediated by immune sensitisation in susceptible individuals to trifluoroacetylated liver protein neoantigens, formed by oxidative halothane metabolism. The seminal event in halothane hepatitis is hepatic metabolism, yet the enzyme responsible for oxidative halothane metabolism and trifluoroacetylated neoantigen formation remains unidentified. This investigation tested the hypothesis that cytochrome P450 2E1 (CYP2E1) is responsible for human halothane metabolism in vivo. METHODS: 20 elective surgical patients received either disulfiram (500 mg orally, n = 10) or nothing (controls, n = 10) the night before surgery. Disulfiram, converted in vivo to an effective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. All patients received standard halothane anaesthesia (1.0% end-tidal, 3 h). Blood halothane and plasma and urine trifluoroacetic acid, bromide, and fluoride concentrations were measured for up to 96 h postoperatively. FINDINGS: Total halothane dose, measured by cumulative end-tidal (3.8 SE 0.1 minimum alveolar concentration hours) and blood halothane concentrations, was similar in the two groups. Plasma concentrations and urinary excretion of trifluoroacetic acid and bromide, indicative of oxidative and total (oxidative and reductive) halothane metabolism, respectively, were significantly diminished in disulfiram-treated patients. In control and disulfiram-treated patients cumulative 96 h postoperative trifluoroacetic acid excretion was 12,900 (SE 1700) and 2010 (440) mumol, respectively (p < 0.001) while that of bromide was 1720 (290) and 160 (70) mumol (p < 0.001). INTERPRETATION: The substantial attenuation of trifluoroacetic acid production by disulfiram after halothane anaesthesia suggests that P450 2E1 is a predominant enzyme responsible for human oxidative halothane metabolism. Inhibition of P450 2E1 by a single preoperative oral disulfiram dose greatly diminished production of the halothane metabolite responsible for the neoantigen formation that initiates halothane hepatitis. Single-dose disulfiram may provide effective prophylaxis against halothane hepatitis.

Regioselectivity and enantioselectivity of metoprolol oxidation by two variants of cDNA-expressed P4502D6.

PURPOSE: The oxidative metabolism of metoprolol was investigated in two human lymphoblastoma cell-lines transfected with variants of cDNA for cytochrome P4502D6. METHODS: The regioselective and enantioselective features of the oxidations of deuterium-labeled pseudoracemic metoprolol were characterized by GC/MS analysis of the substrate and products. RESULTS: There were significant differences between the two P4502D6 variants in the formation kinetics of O-demethylmetoprolol and alpha-hydroxymetoprolol. The h2D6-Val microsomes highly favored the formation of the O-demethylmetoprolol regioisomer 6.3:1 and 2.8:1, respectively from (R)-metoprolol-d0 and (S)-metoprolol-d2, while the corresponding ratios for h2D6v2 microsomes were much lower. For both variants, O-demethylmetoprolol formation favored the (R)-substrate 1.5 to 2-fold, while alpha-hydroxymetoprolol formation was non-enantioselective. Similar Km values of metoprolol oxidation, 10-20 microM, were observed for the two microsomal preparations. CONCLUSIONS: The regioselectivity, enantioselectivity, and Km values for the h2D6-Val microsomes resemble those observed for the native P4502D6 in human liver microsomes, whereas the h2D6v2 microsomes deviated remarkably in regioselectivity.

Epinephrine is metabolized by the spinal meninges of monkeys and pigs.

BACKGROUND: Epinephrine commonly is added to epidural opioids and local anesthetics, however, little is known about the fate of epidurally administered epinephrine. Studies have identified the epinephrine metabolizing enzyme, catechol-O-methyl transferase (COMT), in the cranial meninges of several species. The purpose of this study was to determine whether the spinal meninges also contain COMT and are capable of metabolizing epinephrine. If so, then the spinal meninges may have an important impact in limiting the bioavailability of epinephrine in both the spinal cord and epidural space. METHODS: Spinal meningeal specimens measuring 4 cm2 were obtained from monkeys (M. nemestrina) and farm-bred pigs and were incubated in bicarbonate-buffered mock cerebrospinal fluid. Epinephrine (200 micrograms base) was added at t = 0, and 200 min later, the mock cerebrospinal fluid was collected for metanephrine analysis. In separate experiments, pig meningeal specimens were separated into dura mater, pia-arachnoid mater, and pia mater, and the experiments were repeated to determine which meninx had the greatest COMT activity. RESULTS: Metanephrine was produced by monkey meninges at the rate of 0.47 ng.min-1.cm-2 and by pig meninges at the rate of 0.23 ng.min-1.cm-2 (P > 0.05). The pia-arachnoid meninx produced metanephrine at a greater rate (4.48 +/- 0.46 ng.min-1.mg-1 tissue) than did the pia mater (1.3 +/- 0.15 ng.min-1.mg-1 tissue) or dura mater alone (1.82 +/- 0.23 ng.min-1.mg-1 tissue). CONCLUSIONS: These data demonstrate the functional presence of COMT in the spinal meninges of pigs and monkeys and suggest that the spinal meninges may limit the spinal bioavailability of epidurally or intrathecally administered epinephrine.

Regioselective and stereoselective oxidation of metoprolol and bufuralol catalyzed by microsomes containing cDNA-expressed human P4502D6.

Regioselective and stereoselective oxidations of pseudoracemic metoprolol, (R)-bufuralol, and (S)-bufuralol by microsomes of h2D6v2 cells--a human lymphoblastoma cell line transfected with a cytochrome P4502D6 expression system--were examined. The formation kinetics of O-demethylmetoprolol and alpha-hydroxymetoprolol were characterized in five different lots of the cDNA-expressed P4502D6. Comparison of the Vmax/KM values indicated that formation of the products from (R)-metoprolol was preferred. Although the favored regiomer overall was O-demethylmetoprolol, the regioselectivity for O-demethylation of metoprolol by the cDNA-expressed enzyme was several-fold less than that observed for the P4502D6 enzyme in human liver microsomes at 20 microM pseudoracematic metoprolol concentration. Oxidation of (R)-metoprolol produced more O-demethylmetoprolol than alpha-hydroxymetoprolol; however, for (S)-metoprolol-d2, a slight preference for alpha-hydroxylation was observed. The O-demethylation and alpha-hydroxylation of metoprolol were inhibited at low microM concentrations of (+/-)-verapamil, a known inhibitor of metoprolol oxidation. (R)- and (S)-Bufuralol were oxidized to their respective diastereomeric 1"-hydroxybufuralols by all 4 lots of h2D6v2 microsomal preparations. Diastereomeric (1'R)-hydroxybufuralols were formed in twice the amount as the hydroxylated diastereomers of (1'S)-products. Product stereoselectivity was observed for the (1'R,1"S)- and (1'S,1"R)-isomers. Although the observed enantioselectivity and diastereoselectivity of the bufuralol oxidation seem to be consistent with those previously reported for human liver microsomes, the regioselectivity of the metoprolol oxidations is unexpectedly low.

Determination of alfentanil and noralfentanil in human plasma by gas chromatography-mass spectrometry.

This report describes a simple gas chromatographic-mass spectrometric (GC-MS) assay for the simultaneous analysis of alfentanil and its major metabolite, noralfentanil, in human plasma. The method facilitates the processing of numerous samples for pharmacokinetic analysis. Alfentanil and noralfentanil are extracted from plasma under basic conditions and noralfentanil is converted to the pentafluoropropionyl derivative. The extraction efficiencies for noralfentanil and alfentanil were > 99% and 70%, respectively. Standard curves were linear (r2 = 0.99) over the ranges of 5-500 ng/ml for alfentanil and 0.4-10 ng/ml for noralfentanil. Inter-day coefficients significant improvement over existing HPLC assays which require radiolabelled significant improvement over existing HPLC assays which require radiolabelled alfentanil. The simultaneous disposition of alfentanil and noralfentanil in plasma after intravenous administration in humans is described.

Clinical enflurane metabolism by cytochrome P450 2E1.

BACKGROUND: Fluorinated ether anesthetic hepatotoxicity and nephrotoxicity are mediated by cytochrome P450-catalyzed oxidative metabolism. Metabolism of the volatile anesthetic enflurane to inorganic fluoride ion by human liver microsomes in vitro is catalyzed predominantly by the cytochrome P450 isoform CYP2E1. This investigation tested the hypothesis that P450 2E1 is also the isoform responsible for human enflurane metabolism in vivo. Disulfiram, which is converted in vivo to a selective inhibitor of P450 2E1, was used as a metabolic probe for P450 2E1. METHODS: Twenty patients undergoing elective surgery were randomized to receive disulfiram (500 mg orally; n = 10) or nothing (control subjects; n = 10) the evening before surgery. All patients received a standard anesthetic of enflurane (2.2% end-tidal) in oxygen for 3 hours. Blood enflurane concentrations were measured by gas chromatography. Plasma and urine fluoride concentrations were quantitated by ion-selective electrode. RESULTS: Patient groups were similar with respect to age, weight, gender, duration of surgery, and blood loss. Total enflurane dose, measured by cumulative end-tidal enflurane concentrations (3.9 to 4.1 MAC-hr) and by blood enflurane concentrations, was similar in both groups. Plasma fluoride concentrations increased from 3.6 +/- 1.5 mumol/L (baseline) to 24.3 +/- 3.8 mumol/L (peak) in untreated patients (mean +/- SE). Disulfiram treatment completely abolished the rise in plasma fluoride concentration. Urine fluoride excretion was similarly significantly diminished in disulfiram-treated patients. Fluoride excretion in disulfiram-treated patients was 62 +/- 10 and 61 +/- 12 mumol on days 1 and 2, respectively, compared with 1090 +/- 180 and 1200 +/- 220 mumol in control subjects (p < 0.05 on each day). CONCLUSIONS: Disulfiram prevented fluoride ion production after enflurane anesthesia. These results suggest that P450 2E1 is the predominant P450 isoform responsible for human clinical enflurane metabolism in vivo.