Difference between in vivo and in vitro effects of propofol on defluorination and metabolic activities of hamster hepatic cytochrome P450-dependent mono-oxygenases

We have compared the in vivo and in vitro effects of propofol on cytochrome P450-dependent monooxygenase activities in hamster liver microsomes. Propofol (Diprivan) 10 mg/100 g body weight was injected i.p. twice a day for 2 weeks to induce cytochrome P450 enzymes. Liver microsomes were prepared by differential centrifugation. Metabolism of the cytochrome P450-dependent mono-oxygenase system was evaluated by measuring aniline hydroxylation, benzphetamine demethylation and benzo(a)pyrene hydroxylation. Defluorination of enflurane was assayed by detecting free fluoride metabolites. At similar concentrations as in the in vivo group, propofol in vitro exhibited concentration-dependent inhibition of metabolism of benzphetamine and benzo(a)pyrene. Aniline hydroxylation and defluorination of enflurane were inhibited to 78% of control with propofol 0.25 mmol litre-1. In propofol-treated hamsters, there was only minimal inhibitory or inductive effects on either mono- oxygenase activities or capacity for defluorination. This difference between the in vitro and in vivo effects of propofol on cytochrome P450 mono-oxygenase activities emphasizes the need for care when comparing in vitro and clinical data.      

Human cytochrome P450 mono-oxygenase system is suppressed by propofol

We have studied the effect of propofol on the cytochrome P450-dependentmono-oxygenase system in human liver microsomes by assayingmono-oxygenase activities toward specific cytochrome P450 isoformtest substrates, aniline, 7-ethoxycoumarin, benzphetamine andbenzo(a) pyrene. Propofol inhibited benzo(a)pyrene hydroxylationto a greater extent than the oxidative metabolism of the othertest substrates, even at 0.05 mmol litre^–1 The degreesof inhibition of benzphetamine N-demethylation and 7-ethoxy-coumarinO-de-ethylation were similar, while aniline hydroxylation wasleast affected by propofol. Spectral analysis showed that propofolcompeted with carbon monoxide for binding to the haem moietyof haemoprotein in the P450 enzyme. The variable inhibitionobserved may be caused by the differential binding of propofolto P450 isoforms. Propofol 0.05–1.0 mmol litre^–1exhibited a concentration-dependent inhibitory effect on humancytochrome P450 2E1, 2B1 and 1A1. These inhibitory actions ofpropofol on human liver microsomal enzymes in vitro suggestthat potential drug interactions may exist between propofoland other drugs administered clinically. (Br. J. Anaesth. 1995;74: 558–562)     

Human Kidney Methoxyflurane and Sevoflurane Metabolism: Intrarenal Fluoride Production as a Possible Mechanism of Methoxyflurane Nephrotoxicity

Background: Methoxyflurane nephrotoxicity is mediated by cytochrome P450-catalyzed metabolism to toxic metabolites. It is historically accepted that one of the metabolites, fluoride, is the nephrotoxin, and that methoxyflurane nephrotoxicity is caused by plasma fluoride concentrations in excess of 50 micro Meter. Sevoflurane also is metabolized to fluoride ion, and plasma concentrations may exceed 50 micro Meter, yet sevoflurane nephrotoxicity has not been observed. It is possible that in situ renal metabolism of methoxyflurane, rather than hepatic metabolism, is a critical event leading to nephrotoxicity. We tested whether there was a metabolic basis for this hypothesis by examining the relative rates of methoxyflurane and sevoflurane defluorination by human kidney microsomes.

Methods: Microsomes and cytosol were prepared from kidneys of organ donors. Methoxyflurane and sevoflurane metabolism were measured with a fluoride-selective electrode. Human cytochrome P450 isoforms contributing to renal anesthetic metabolism were identified by using isoform-selective inhibitors and by Western blot analysis of renal P450s in conjunction with metabolism by individual P450s expressed from a human hepatic complementary deoxyribonucleic acid library.

Results: Sevoflurane and methoxyflurane did undergo defluorination by human kidney microsomes. Fluoride production was dependent on time, reduced nicotinamide adenine dinucleotide phosphate, protein concentration, and anesthetic concentration. In seven human kidneys studied, enzymatic sevoflurane defluorination was minimal, whereas methoxyflurane defluorination rates were substantially greater and exhibited large interindividual variability. Kidney cytosol did not catalyze anesthetic defluorination. Chemical inhibitors of the P450 isoforms 2E1, 2A6, and 3A diminished methoxyflurane and sevoflurane defluorination. Complementary deoxyribonucleic acid-expressed P450s 2E1, 2A6, and 3A4 catalyzed methoxyflurane and sevoflurane metabolism, in diminishing order of activity. These three P450s catalyzed the defluorination of methoxyflurane three to ten times faster than they did that of sevoflurane. Expressed P450 2B6 also catalyzed methoxyflurane defluorination, but 2B6 appeared not to contribute to renal microsomal methoxyflurane defluorination because the P450 2B6-selective inhibitor had no effect.     

Effects of propofol on functional activities of hepatic and extrahepatic conjugation enzyme systems

The effect of propofol on the hepatic and extrahepatic conjugationenzyme systems was assessed in vitro using microsomal and cytosolicpreparations of human liver, hamster kidney, lung and gut. Thefunctional activities of phase-II enzymes, including uridinediphosphate-glucuronosyltransferase (UDPGT), glutathione S-transferase(GST) and N-acetyltransferase (NAT) were evaluated in the presenceof various concentrations of propofol (0.05–1.0 mmol litre^–1),using 1-naphthol, 1-chloro-2,4-dinitrobenzene and p-aminobenzoicacid as substrates respectively. Propofol produced concentration-dependentinhibition of UDPGT activity in human liver microsomes. Propofoldid not produce significant inhibition of human hepatic GSTactivity at concentrations below 1.0 mmol litre^–1. Incontrast, NAT activity was unaffected by propofol 0.05–1.0mmol litre^–1 in human liver cytosolic preparations. Inextrahepatic tissues, hamster renal and intestinal UDPGT activitieswere significantly inhibited by propofol at 0.25–1.0 mmollitre^–1. In these tissues, GST and NAT were unaffectedby propofol at 1.0 mmol litre^–1. Propofol produced differentialinhibition of human liver and hamster extrahepatic conjugationenzymes as a result of different substrate and tissue specificities.The potential interference of the metabolic profile of phase-IIenzymes as a result of inhibition by propofol (especially ofUDPGT and GST) should be considered when using propofol withother drugs for anaesthesia.     

Oxygen concentrations required for reductive defluorination of halothane by rat hepatic microsomes

The free oxygen concentrations required for reductive defluorination of halothane by rat hepatic microsomes from control and phenobarbital- (PB) and polychlorinated biphenyl-(PCB) treated animals were determined. Halothane-exposed microsomes from treated rats generated measurable levels of fluoride ion after 30 min incubations with oxygen concentrations of 5% or less. Microsomes from control animals produced fluoride only if the free oxygen concentration was 2% or less. During anoxic (0% oxygen) incubations, defluorination rates of 2.10 +/- 0.17, 5.55 +/- 0.38, and 5.46 +/- 0.30 nmol fluoride X mg protein-1 X 30 min-1 were observed for microsomes from control, PB, and PCB rats, respectively. Normalizing the maximal rates of defluorination to the microsomal cytochrome P-450 content yielded values of 5.14 +/- 1.40, 3.70 +/- 0.15, and 2.38 +/- 0.26 nmol fluoride X nmol cytochrome P-450-1 X 30 min-1 for control, PB, and PCB microsomes, respectively. Oxygen concentrations required for reductive metabolism of halothane by isolated rat hepatic microsomes are close to normal physiologic free oxygen concentrations of 4-5% reported for centrilobular areas of the rat liver. Thus even slight reductions in hepatic oxygenation during anesthetic exposure could lead to enhanced reductive biotransformation, an observation found in rat models of halothane-associated hepatic injury. The large differences among the treatment groups in the rates of fluoride ion generated per nanomole cytochrome P-450 indicate that enzyme induction regimens disproportionately increase those isozymes of hepatic cytochrome P-450 that are not involved with the reductive defluorination of halothane.     

Propofol attenuates acetylcholine-induced pulmonary vasorelaxation: role of nitric oxide and endothelium-derived hyperpolarizing factors

BACKGROUND: The mechanism by which propofol selectively attenuates the pulmonary vasodilator response to acetylcholine is unknown. The goals of this study were to identify the contributions of endogenous endothelial mediators (nitric oxide [NO], prostacyclin, and endothelium-derived hyperpolarizing factors [EDHFs]) to acetylcholine-induced pulmonary vasorelaxation, and to delineate the extent to which propofol attenuates responses to these endothelium-derived relaxing factors. METHODS: Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of propofol on the vasorelaxation responses to acetylcholine, bradykinin, and the guanylyl cyclase activator, SIN-1, were assessed in phenylephrine-precontracted rings. The contributions of NO, prostacyclin, and EDHFs to acetylcholine-induced vasorelaxation were assessed in control and propofol-treated rings by pretreating the rings with a NO synthase inhibitor (l-NAME), a cyclooxygenase inhibitor (indomethacin), and a cytochrome P450 inhibitor (clotrimazole or SKF 525A) alone and in combination. RESULTS: Propofol caused a dose-dependent rightward shift in the acetylcholine dose-response relation, whereas it had no effect on the pulmonary vasorelaxant responses to bradykinin or SIN-1. Cyclooxygenase inhibition only attenuated acetylcholine-induced relaxation at high concentrations of the agonist. NO synthase inhibition and cytochrome P450 inhibition each attenuated the response to acetylcholine, and combined inhibition abolished the response. Propofol further attenuated acetylcholine-induced relaxation after NO synthase inhibition and after cytochrome P450 inhibition. CONCLUSION: These results suggest that acetylcholine-induced pulmonary vasorelaxation is mediated by two components: NO and a cytochrome P450 metabolite likely to be an EDHF. Propofol selectively attenuates acetylcholine-induced relaxation by inhibiting both of these endothelium-derived mediators.     

Propofol Attenuates Acetylcholine-induced Pulmonary Vasorelaxation: Role of Nitric Oxide and Endothelium-derived Hyperpolarizing Factors

Background: The mechanism by which propofol selectively attenuates the pulmonary vasodilator response to acetylcholine is unknown. The goals of this study were to identify the contributions of endogenous endothelial mediators (nitric oxide [NO], prostacyclin, and endothelium-derived hyperpolarizing factors [EDHFs]) to acetylcholine-induced pulmonary vasorelaxation, and to delineate the extent to which propofol attenuates responses to these endothelium-derived relaxing factors.

Methods: Canine pulmonary arterial rings were suspended for isometric tension recording. The effects of propofol on the vasorelaxation responses to acetylcholine, bradykinin, and the guanylyl cyclase activator, SIN-1, were assessed in phenylephrine-precontracted rings. The contributions of NO, prostacyclin, and EDHFs to acetylcholine-induced vasorelaxation were assessed in control and propofol-treated rings by pretreating the rings with a NO synthase inhibitor (l-NAME), a cyclooxygenase inhibitor (indomethacin), and a cytochrome P450 inhibitor (clotrimazole or SKF 525A) alone and in combination.

Results: Propofol caused a dose-dependent rightward shift in the acetylcholine dose-response relation, whereas it had no effect on the pulmonary vasorelaxant responses to bradykinin or SIN-1. Cyclooxygenase inhibition only attenuated acetylcholine-induced relaxation at high concentrations of the agonist. NO synthase inhibition and cytochrome P450 inhibition each attenuated the response to acetylcholine, and combined inhibition abolished the response. Propofol further attenuated acetylcholine-induced relaxation after NO synthase inhibition and after cytochrome P450 inhibition.     

Effects of propofol on isolated rabbit mesenteric arteries and veins

We have investigated the effect of propofol on isolated rabbit mesenteric arteries and veins. Isometric tension was measured in rings of arteries (with or without endothelium) or veins in organ chambers. The preparation was stimulated with noradrenaline 10(-6) mol litre-1, K+ 50 mmol litre-1 and caffeine 20 mmol litre-1 in the presence or absence of propofol. Propofol potentiated noradrenaline-induced contractions at lower concentrations (3 x 10(-5) mol litre-1) and attenuated them at greater concentrations (10(-4) and 3 x 10(-4) mol litre-1) in arteries with endothelium. Propofol inhibited noradrenaline- induced contractions in arteries without endothelium. In contrast, propofol produced venodilatation in a concentration-dependent manner (10(-5) to 3 x 10(-4) mol litre-1) of significantly greater magnitude than that in arteries. Propofol inhibited K+-induced contraction of both arteries and veins. It decreased the relaxation induced by acetylcholine (3 x 10(-8), 10(-7) and 3 x 10(-7) mol litre-1) of noradrenaline-induced contractions of arteries. Propofol did not affect caffeine-induced contractions after pretreatment with increased Ca2+. We conclude that propofol has a more potent vasodilator effect on veins than on arteries. Vasoconstriction induced by propofol may be associated with inhibition of endothelium-derived relaxing factor, whereas vasodilatation induced by propofol may be associated with block of voltage-gated influxes of extracellular Ca2+.      

Propofol/sufentanil anesthesia suppresses the metabolic and endocrine response during, not after, lower abdominal surgery

We investigated the influence of propofol/sufentanil anesthesia on metabolic and endocrine responses during, and immediately after, lower abdominal surgery. Twenty otherwise healthy patients undergoing abdominal hysterectomy for benign myoma received either continuous infusions of propofol supplemented with sufentanil (0.01 microg. kg(-1). min(-1), n = 10) or enflurane anesthesia (enflurane, n = 10). Plasma concentrations of glucose, lactate, free fatty acids, triglycerides, insulin, glucagon, cortisol, epinephrine, and norepinephrine were measured before, during, and 2 h after surgery. Pre- and postoperative endogenous glucose production (R(a) glucose) was analyzed by an isotope dilution technique by using [6,6-(2)H(2)] glucose. Propofol/sufentanil anesthesia prevented the increase in plasma cortisol and catecholamine concentrations and attenuated the hyperglycemic response during surgery without showing any difference after the operation. Mediated through a higher glucagon/insulin quotient (propofol/sufentanil 15 +/- 7 versus enflurane 8 +/- 4 pg/microU, P < 0.05), the R(a) glucose postoperatively increased more in the propofol/sufentanil than in the enflurane group (propofol/sufentanil 15.6 +/- 2.0 versus enflurane 13.4 +/- 2.2 micromol. kg(-1). min(-1), P < 0.05). IMPLICATIONS: The concept of stress-free anesthesia using propofol combined with sufentanil is valid only during surgery. The metabolic endocrine stress response 2 h after the operation is more pronounced than after inhaled anesthesia.     

Cytochrome P-450 2B6 is responsible for interindividual variability of propofol hydroxylation by human liver microsomes

BACKGROUND: Oxidation of propofol to 4-hydroxypropofol represents a significant pathway in the metabolism of this anesthetic agent in humans. The aim of this study was to identify the principal cytochrome P-450 (CYP) isoforms mediating this biotransformation. METHODS: Propofol hydroxylation activities and enzyme kinetics were determined using human liver microsomes and cDNA-expressed CYPs. CYP-specific marker activities and CYP2B6 protein content were also quantified in hepatic microsomes for correlational analyses. Finally, inhibitory antibodies were used to ascertain the relative contribution of CYPs to propofol hydroxylation by hepatic microsomes. RESULTS: Propofol hydroxylation by hepatic microsomes showed more than 19-fold variability and was most closely correlated to CYP2B6 protein content (r = 0.904), and the CYP2B6 marker activities, S-mephenytoin N-demethylation (r = 0.919) and bupropion hydroxylation (r = 0.854). High- and intermediate-activity livers demonstrated high-affinity enzyme kinetics (K(m) < 8 microm), whereas low-activity livers displayed low-affinity kinetics (K(m) > 80 microm). All of the CYPs evaluated were capable of hydroxylating propofol; however, CYP2B6 and CYP2C9 were most active. Kinetic analysis indicated that CYP2B6 is a high-affinity (K(m) = 10 +/- 2 microm; mean +/- SE of the estimate), high-capacity enzyme, whereas CYP2C9 is a low-affinity (K(m) = 41 +/- 8 microm), high-capacity enzyme. Furthermore, immunoinhibition showed a greater contribution of CYP2B6 (56 +/- 22% inhibition; mean +/- SD) compared with CYP2C isoforms (16 +/- 7% inhibition) to hepatic microsomal activity. CONCLUSIONS: Cytochrome P-450 2B6, and to a lesser extent CYP2C9, contribute to the oxidative metabolism of propofol. However, CYP2B6 is the principal determinant of interindividual variability in the hydroxylation of this drug by human liver microsomes.     

Effect of propofol on ropivacaine metabolism in human liver microsomes

A combination of the general anesthestic propofol and epidural anesthesia with a local anesthetic is widely used. The metabolism of ropivacaine and that of lidocaine are mediated by similar P450 isoforms. Previously, propofol was found to inhibit the metabolism of lidocaine in vitro. Here we investigated whether propofol inhibits the metabolism of ropivacaine using human liver microsomes in vitro. Ropivacaine (6.0 μmol·l⁻¹) as the substrate and propofol (1–100 μmol·l⁻¹) were reacted together using human microsomes. The concentrations of ropivacaine and its major metabolite 2′,6′-pipecoloxylidide (PPX) were measured using high-performance liquid chromatography. The metabolic activity of ropivacaine was reflected in the production of PPX. The inhibitory effects of propofol on ropivacaine metabolism were observed to be dose-dependent. The IC₅₀ of propofol was 34.9 μmol·l⁻¹. Propofol shows a competitive inhibitory effect on the metabolism of ropivacaine (i.e., PPX production mediated by CYP3A4) in human CYP systems in vitro.     

ETHANOL-INDUCIBLE CYTOCHROME P450 IN RABBITS METABOLIZES ENFLURANE

Following anaesthesia with enflurane, some patients receivingisoniazid have increased serum concentrations of fluoride ion,presumably because of induction of an isozyme of cytochromeP450 which is responsible for enflurane biodegradation. In rats,isoniazid and ethanol enhance metabolism of enflurane and alsoinduce a form of cytochrome P450 which is homologous with aform of rabbit liver cytochrome P450 known as 3a. Isoniazid,ethanol and imidazole increase the concentration of cytochromeP450 3a in hepatic microsomes. We have pretreated rabbits withimidazole, the most potent of the three inducers of isozyme3a, to determine if the hepatic microsomal metabolism of enfluraneis enhanced and if purified isozyme 3a catalyses the oxidationof enflurane. Imidazole produced a 250% increase in the hepaticmicrosomal metabolism of enflurane, sevoflurane, methoxyfluraneand the control substrate, aniline. Polyclonal antibodies tocytochrome P450 3a inhibited 90% of enflurane metabolism, butonly 40 % of methoxyflurane biotransformation in the microsomesfrom imidazole-pretreated rabbits. Thus isozyme 3a or a structurallysimilar cytochrome P450 seemed to catalyse almost all microsomalmetabolism of enflurane. In addition, purified cytochrome P4503a catalysed the metabolism of enflurane, sevoflurane and methoxyflurane,and the oxidation of these anaesthetics by cytochrome P450 3awas stimulated four-fold by cytochrome b₅, a protein which servesas an alternate source of electrons for some cytochrome P450reactions. A preliminary report of these results was published in Anesthesiology1986; 65: A232.     

DRUG METABOLIZING ENZYMES IN THE RAT AFTER INHALATION OF HALOTHANE AND ENFLURANE: Different pattern of response in liver, kidney and lung and possible implications for toxicity

Male Sprague-Dawley rats were exposed in inhalation chambersto halothane and enflurane in concentrations from 50 to 1000p.p.m. (0.0025 MAC-0.05MAC) 6 h a day for 3–11 days. Nosigns of general toxicity were found. There was a normal increasein weight, and normal food consumption, organ to body weightratios and normal histological findings in liver, kidney andlung. Exposure to 500 p.p.m. (0.05 MAC) of halothane inducedthe activity of NADPH-cytochrome-c-reductase in the liver, decreasedthe concentration of cytochrome P-450 in the kidney and decreasedall the enzyme concentrations measured in lung microsomes. Exposureto halothane 50 p.p.m. (0.005 MAC) and enflurane produced onlyminor changes. It is concluded that the inhalation of halothane,in contrast to enflurane, may affect drug metabolism and therebydrug kinetics and toxicity. Halothane may increase its own toxicityby increasing the activity of NADPH-cytochrome-c-reductase inliver. An organ differentiation in enzymatic response was observed.     

Cytochrome P450-dependent arachidonic acid metabolism in human kidney

Cytochrome P450-dependent arachidonic acid metabolism in human kidney cortex from several postmortem subjects has been characterized. Using HPLC and GC/MS, four cytochrome P450-arachidonic acid metabolites were tentatively but not unequivocally identified as epoxyeicosatrienoic acid (EET), dihydroxyeicosatrienoic acid (DHT) and 19- and 20-hydroxyeicosatetraenoic acids, suggesting the involvement of two major cytochrome P450 enzymes, epoxygenase and omega/omega-1 hydroxylases. This pattern of metabolism was similar to that found in rabbit and rat kidneys. The formation of these metabolites was dependent on the presence of NADPH and inhibited by IgG of NADPH-cytochrome P450 (c) reductase. Immunologic studies of renal cytochrome P450 epoxygenase demonstrated that antibodies prepared against human-purified hepatic cytochrome P450 epoxygenase recognized renal enzyme protein and inhibited the enzyme activity by 92%. In contrast, control immunoglobulin did not inhibit renal cytochrome P450 epoxygenase. Antibody inhibition of renal cytochrome P450 epoxygenase demonstrated a degree of conservation of both enzyme proteins between liver and kidney. Antibodies against lauric acid omega/omega-1 hydroxylases (P450 omega) inhibited the formation of omega/omega-1 hydroxylase products, 19- and 20-HETEs. Identical qualitative patterns of arachidonic acid metabolites were observed in all cortical microsomes studied. Interindividual variations were observed in the cytochrome P450-dependent arachidonic acid metabolism, and the activities ranged from 0.031 to 5.027 nmol arachidonic acid converted/mg protein/30 min. which is about a 150-fold difference. However, when the specific activities for total cytochrome P450-dependent arachidonic acid metabolism were calculated, two separate groups could be distinguished, high and low metabolizers of arachidonic acid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytochrome P-450 2B6 Is Responsible for Interindividual Variability of Propofol Hydroxylation by Human Liver Microsomes

Background: Oxidation of propofol to 4-hydroxypropofol represents a significant pathway in the metabolism of this anesthetic agent in humans. The aim of this study was to identify the principal cytochrome P-450 (CYP) isoforms mediating this biotransformation.

Methods: Propofol hydroxylation activities and enzyme kinetics were determined using human liver microsomes and cDNA-expressed CYPs. CYP-specific marker activities and CYP2B6 protein content were also quantified in hepatic microsomes for correlational analyses. Finally, inhibitory antibodies were used to ascertain the relative contribution of CYPs to propofol hydroxylation by hepatic microsomes.

Results: Propofol hydroxylation by hepatic microsomes showed more than 19-fold variability and was most closely correlated to CYP2B6 protein content (r = 0.904), and the CYP2B6 marker activities, S-mephenytoin N-demethylation (r = 0.919) and bupropion hydroxylation (r = 0.854). High- and intermediate-activity livers demonstrated high-affinity enzyme kinetics (Km < 8 [mu]m), whereas low-activity livers displayed low-affinity kinetics (Km > 80 [mu]m). All of the CYPs evaluated were capable of hydroxylating propofol; however, CYP2B6 and CYP2C9 were most active. Kinetic analysis indicated that CYP2B6 is a high-affinity (Km = 10 +/- 2 [mu]m; mean +/- SE of the estimate), high-capacity enzyme, whereas CYP2C9 is a low-affinity (Km = 41 +/- 8 [mu]m), high-capacity enzyme. Furthermore, immunoinhibition showed a greater contribution of CYP2B6 (56 +/- 22% inhibition; mean +/- SD) compared with CYP2C isoforms (16 +/- 7% inhibition) to hepatic microsomal activity.     

The influence of volatile anaesthetics on drug metabolism in the liver (author's transl)]

In Vitro experiments with rat liver microsomes (difference spectra, p-nitroanisol-demethylation) and in vivo experiments with rats (tritium release from 3H-mestranol) suggest an inhibition of the metabolism of certain drugs (type-1-substrates) by competition for the binding site of cytochrome P-450 under anaesthesia with diethyl ether, halothane, enflurane and methoxyflurane.     

The effect of propofol on midazolam metabolism in human liver microsome suspension

We have studied the inhibitory effects of propofol on the metabolism of midazolam using human liver microsomes. In addition, we also investigated whether the lipid in which propofol is solubilised inhibits the metabolism of midazolam. Only high concentrations of propofol (>100 mmol), greater than those found in clinical practice, inhibited the metabolism of midazolam. The lipid had no effect on the metabolism of midazolam. This study differs from other laboratory studies looking at the inhibitory effects of propofol. These showed inhibition at concentrations similar to those seen in patients. The reasons for the differences may be explained by the use of different substrates or methodology. Propofol may be an enzyme inhibitor, but this remains to be shown to be important in patients.     

The influence of hypoxia and hyperoxia on the kinetics of propofol emulsion

PURPOSE: To study the effect of hypoxia and hyperoxia on the pharmacokinetics of propofol emulsion, hepatic blood flow and arterial ketone body ratio in the rabbit. METHODS: Twenty four male rabbits were anesthetized with isoflurane (1.5-2%) in oxygen. After the surgical procedure, isoflurane administration was discontinued and intravenous propofol infusion (30 mg x kg(-1) x hr(-1)) was started. The infusion rate of propofol was maintained throughout the study. After an initial 90 min period of propofol infusion, rabbits were randomly allocated to one of three groups: hypoxia (F(I)O2 = 0.1), normoxia (F(I)O2 = 0.21), and hyperoxia (F(I)O2 = 1.0). Propofol infusion was continued under the allocated F(I)O2 for 60 min. Propofol concentrations in arterial blood, total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were measured. RESULTS: The mean arterial propofol concentration at the end of infusion was higher in the hypoxia group (15.2 +/- 2.8 microg x mL(-1), mean +/- SD) than in the normoxia (7.4 +/- 1.7) and hyperoxia (8.0 +/- 1.9) groups (P < 0.05). Total body clearance of propofol, hepatic blood flow and arterial ketone body ratio were all reduced in the hypoxia group (P < 0.05). Total ketone body concentration in arterial blood increased in the hyperoxia group (P < 0.01). CONCLUSION: Hypoxia produced an accumulation of propofol in blood and reduced propofol clearance. These changes could result from decreased hepatic blood flow and low cellular energy charge in the liver. Hyperoxia, on the other hand, increased total ketone body in arterial blood.     

The independent effect of propofol anesthesia on whole body protein metabolism in humans.

BACKGROUND: The purpose of this study was to examine the effect of general anesthesia with propofol in the absence of surgical stimulation on whole body protein metabolism. METHODS: Six unpremedicated patients were studied. General anesthesia included propofol (120 microg x kg(-1) x min(-1)), vecuronium bromide, and oxygen-enriched air. Changes in protein breakdown, protein oxidation, and synthesis were measured by an isotope dilution technique using a constant infusion of the stable isotope tracer L-[1-13C]leucine (0.008 mg x kg(-1) x min(-1)) before and during 100 min of propofol anesthesia. The plasma concentrations of glucose, lactate, non-esterified fatty acids, and cortisol were measured before and during anesthesia. RESULTS: An isotopic steady state of plasma [1-13C]alpha-ketoisocaproate (taken to represent the intracellular leucine precursor pool enrichment for protein synthesis) and expired 13C-carbon dioxide were obtained before and during propofol infusion. Whole body protein breakdown decreased during propofol anesthesia by 6% (P < 0.05), whereas protein synthesis and oxidation did not change significantly. Plasma concentration of cortisol decreased after 90 min of propofol anesthesia (P < 0.05). No significant changes of plasma concentrations of glucose, lactate, and non-esterified fatty acids occurred during propofol administration. CONCLUSIONS: Propofol anesthesia did not significantly affect whole body protein synthesis and oxidation but caused a small, although significant, decrease in whole body protein breakdown, possibly mediated through the suppression of plasma cortisol concentration.     

Comparative study between propofol in a long-chain triglyceride and propofol in a medium/long-chain triglyceride during sedation with target-controlled infusion

This study was performed to compare the pharmacological characteristics of propofol in an emulsion of both medium- and long-chain triglycerides (MCT/LCT) with those of propofol in an LCT emulsion, by measuring the sedative level and the plasma concentration of propofol during sedation using a target-controlled infusion (TCI) technique. Forty ASA 1 or 2 adult patients who required spinal anaesthesia for surgery were enrolled in this study. The patients were divided into two groups: a propofol LCT group (n = 20) and a propofol MCT/LCT group (n = 20). Propofol was injected intravenously at target blood concentrations of 2.0, 3.0 and 4.0 microg x ml(-1). The bispectral (BIS) index was recorded, and arterial blood was drawn to measure the actual plasma concentrations of propofol at each predicted concentration. Propofol was assayed by high-performance liquid chromatography. Propofol MCT/LCT was associated with significantly less pain than propofol LCT (P < 0.05). There were no significant differences between the two groups in BIS index or in plasma concentration of propofol at each predicted concentration. Computer-generated TCI of propofol MCT/LCT during sedation is comparable with that of propofol LCT with respect to pharmacokinetics and pharmacodynamics. The formulation of MCT/LCT has a beneficial effect with respect to less pain on injection.