RESUMO
Neutrophil extracellular traps (NETs) are important components of innate immunity. Neonatal neutrophils (polymorphonuclear leukocytes [PMNs]) fail to form NETs due to circulating NET-inhibitory peptides (NIPs), cleavage fragments of α1-antitrypsin (A1AT). How fetal and neonatal blood NIPs are generated remains unknown, however. The placenta expresses high-temperature requirement serine protease A1 (HTRA1) during fetal development, which can cleave A1AT. We hypothesized that placentally expressed HTRA1 regulates the formation of NIPs and that NET competency changed in PMNs isolated from neonatal HTRA1 knockout mice (HTRA1-/-). We found that umbilical cord blood plasma has elevated HTRA1 levels compared with adult plasma and that recombinant and placenta-eluted HTRA1 cleaves A1AT to generate an A1AT cleavage fragment (A1ATM383S-CF) of molecular weight similar to previously identified NIPs that block NET formation by adult neutrophils. We showed that neonatal mouse pup plasma contains A1AT fragments that inhibit NET formation by PMNs isolated from adult mice, indicating that NIP generation during gestation is conserved across species. Lipopolysaccharide-stimulated PMNs isolated from HTRA1+/+ littermate control pups exhibit delayed NET formation after birth. However, plasma from HTRA1-/- pups had no detectable NIPs, and PMNs from HTRA1-/- pups became NET competent earlier after birth compared with HTRA1+/+ littermate controls. Finally, in the cecal slurry model of neonatal sepsis, A1ATM383S-CF improved survival in C57BL/6 pups by preventing pathogenic NET formation. Our data indicate that placentally expressed HTRA1 is a serine protease that cleaves A1AT in utero to generate NIPs that regulate NET formation by human and mouse PMNs.
Assuntos
Armadilhas Extracelulares/metabolismo , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Placenta/metabolismo , alfa 1-Antitripsina/metabolismo , Animais , Feminino , Humanos , Camundongos Endogâmicos C57BL , Gravidez , ProteóliseRESUMO
Mammals are metagenomic in that they are composed of not only their own gene complements but also those of all of their associated microbes. To understand the coevolution of the mammals and their indigenous microbial communities, we conducted a network-based analysis of bacterial 16S ribosomal RNA gene sequences from the fecal microbiota of humans and 59 other mammalian species living in two zoos and in the wild. The results indicate that host diet and phylogeny both influence bacterial diversity, which increases from carnivory to omnivory to herbivory; that bacterial communities codiversified with their hosts; and that the gut microbiota of humans living a modern life-style is typical of omnivorous primates.
Assuntos
Bactérias/classificação , Fenômenos Fisiológicos Bacterianos , Evolução Biológica , Dieta , Trato Gastrointestinal/microbiologia , Mamíferos/microbiologia , Filogenia , Adaptação Fisiológica , Animais , Animais Selvagens/classificação , Animais Selvagens/genética , Animais Selvagens/microbiologia , Animais de Zoológico/classificação , Animais de Zoológico/genética , Animais de Zoológico/microbiologia , Bactérias/genética , Bactérias/isolamento & purificação , Carnívoros/classificação , Carnívoros/genética , Carnívoros/microbiologia , Fezes/microbiologia , Genes de RNAr , Humanos , Mamíferos/classificação , Mamíferos/genética , Dados de Sequência Molecular , Primatas/classificação , Primatas/genética , Primatas/microbiologia , RNA Ribossômico 16S/genéticaRESUMO
D-Sorbitol (SOR) is safe, is easy to measure, and has an exceptionally high extraction ratio in the normal liver of 0.93+/-0.05 (mean+/-SD). Together with the general interest in hepatic hemodynamics, these facts motivated us to review the usefulness of this compound for the assessment of liver plasma flow in humans. We concluded that in subjects without liver disease the nonrenal clearance of SOR-measured noninvasively-very closely approximates hepatic plasma flow. Because of its lower and more variable extraction ratio, indocyanine green should no longer be used without hepatic vein catheterization. Even in patients with cirrhosis, SOR exhibits higher hepatic extraction ratios than indocyanine green. To fully explore the potential of SOR in the evaluation of such patients attention needs to be paid to the complex changes in architecture and function occurring in this disease. In cirrhotics the noninvasively measured nonrenal clearance of SOR presumably approximates the flow through intact and capillarized sinusoids (functional flow) and reflects the amount of blood having functional contact with hepatocytes. The theoretic background of the method, its accuracy, further research needs, and potentials of various approaches are discussed in detail.
Assuntos
Indicadores e Reagentes/farmacocinética , Circulação Hepática/fisiologia , Sorbitol/farmacocinética , Corantes/farmacocinética , Humanos , Verde de Indocianina/farmacocinética , Fígado/metabolismo , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Métodos , Valores de Referência , Terminologia como AssuntoRESUMO
Quantitative liver function tests such as the determination of galactose elimination capacity (GEC) or the aminopyrine breath test (ABT) may have the potential to serve as refined entry criteria and surrogate markers for end-points in controlled clinical trials. The magnitude of a statistically detectable difference in test results and the period of observation required to document such a difference must be known to properly design such trials. Therefore, we explored retrospectively the time course of changes in GEC and ABT and their reproducibility from a cohort of patients with alcoholic cirrhosis followed for 12 to 42 months, with a median of 34 months. In 15 patients who stopped drinking, GEC improved significantly by 0.64 mg/min/kg within 1 year (mean; 95% confidence interval [CI]: 0.42; 0.86). In contrast, it deteriorated by 0.53 mg/min/kg within 1 year (95% CI: 0.32; 0.74) in another 17 patients who continued to drink (P < .01). The residual standard deviation of the changes in GEC with respect to the patients' initial values was 0.43 mg/min/kg (95% CI: 0.32; 0.52). In addition, ABT improved significantly by 0.14% dose x kg/mmol CO2 (95% CI: 0.09; 0.18) in the abstinent group, and deteriorated by 0.09% dose x kg/mmol CO2 (95% CI: 0.06; 0.13) in the nonabstinent group (P < .01). The residual standard deviation in the above sense for ABT was 0.08% dose x kg/mmol CO2 (95% CI: 0.06; 0.10). These data indicate that clinical trials with a sample size of n = 20 in each group must achieve absolute differences (ADs) in GEC of 0.6 mg/min/kg and of 0.7 mg/min/kg to reach statistical significance at the 5% and 1% level, respectively. In the present study, a period of 11 and 12 months was necessary to observe such differences. The corresponding results for the ABT are 0.11% dose x kg/mmol CO2 (9 months of follow-up; 5% level) and 0.13% dose x kg/mmol CO2 (11 months of observation; 1% level), respectively. Provided that patients with liver diseases treated with drugs are similar to the abstinent and nonabstinent patients with alcoholic liver disease investigated in this study, such numbers could serve for the planning of controlled clinical trials, in which the control group is likely to deteriorate and the treated group is expected to improve. Trials based on GEC or ABT would require only 37 or 30 patient years of observation compared with a median of 444 patient years (range, 50-2,100 patient years) reported for various published controlled clinical trials using survival analysis.
Assuntos
Aminopirina , Testes Respiratórios/métodos , Ensaios Clínicos Controlados como Assunto/normas , Galactose , Cirrose Hepática Alcoólica/fisiopatologia , Testes de Função Hepática , Fígado/fisiopatologia , Adulto , Idoso , Consumo de Bebidas Alcoólicas/fisiopatologia , Análise de Variância , Biomarcadores , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos , TemperançaAssuntos
Anti-Infecciosos/farmacocinética , Infecções Bacterianas/metabolismo , Ciprofloxacina/farmacocinética , Diarreia/metabolismo , Doença Aguda , Área Sob a Curva , Infecções Bacterianas/tratamento farmacológico , Disponibilidade Biológica , Diarreia/tratamento farmacológico , Feminino , Humanos , MasculinoRESUMO
Enrichment in hippurate has been measured to indicate precursor enrichment during glycine tracer infusion studies to estimate fractional synthetic rates of individual hepatic export proteins. However, hippurate tends to overestimate precursor enrichment. Since glycine is rapidly converted to serine by liver cells, we compared tracer enrichment in hippurate and serine with that of glycine incorporated into apolipoprotein (apo) B-100. Ten healthy control subjects were studied in the postabsorptive state during an 8-hour primed-constant infusion of [15N]glycine (10 mumol.kg-1.h-1). Apo B of very-low-density lipoprotein (VLDL) was isolated by standard ultracentrifugation and isopropanol precipitation. Glycine and serine were isolated from plasma and hydrolyzed apo B, hippurate was isolated from plasma, and [15N]enrichment was determined by gas chromatography-mass spectrometry. Enrichment in serine and glycine isolated from apo B was identical at all time points, and their enrichment in apo B increased asymptotically, approaching an apparent plateau (mean +/- SD: 91% +/- 10% of calculated plateau at 8 hours) that was taken to represent hepatic protein precursor enrichment. Enrichment in both plasma serine and hippurate followed a biphasic pattern and continued to increase until the end of the study, raising the possibility that precursor enrichment had not reached a steady state during the study. The apo B plateau was lower (factor 0.76 +/- 0.27) than the final enrichment in hippurate and higher (factor 1.38 +/- 0.36) than that in plasma serine; however, predictions of protein precursor enrichment based on either metabolite were flawed by a large coefficient of variation (35% v 26%).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Apolipoproteínas B/metabolismo , Glicina/metabolismo , Hipuratos/metabolismo , Lipoproteínas VLDL/metabolismo , Serina/metabolismo , Adulto , Apolipoproteínas B/análise , Cromatografia Gasosa-Espectrometria de Massas , Glicina/análise , Hipuratos/análise , Hipuratos/sangue , Humanos , Lipoproteínas VLDL/análise , Masculino , Isótopos de Nitrogênio , Serina/análise , Serina/sangue , Fatores de TempoRESUMO
Various methods of gentamicin dosing were compared in order to evaluate factors that prevent achievement of therapeutic peak and trough plasma concentrations in every patient. When standard doses of 3 x 80 mg of gentamicin/day (i.e., 3 x 170 mumol/day) were administered, only 26% of peak and 51% of trough plasma concentrations were within the desired range. This percentage increased for peak levels to 54% (p less than 0.001) when physicians were instructed in the use of a programmed pocket calculator (PPC) and to 70% (p less than 0.001) when in addition the nursing staff was trained. The best results were achieved when dosing and blood sampling were supervised by a single trained person, 76% of initial peak and 71% of initial trough levels being within the therapeutic range. In this group of patients, further dosage adjustments by the PPC achieved 92% of peak levels in the desired range, while no patient had elevated trough levels. Analysis of the factors that led to these results revealed that neither the laboratory nor the PPC are limiting factors for optimal results. The goal of therapeutic plasma concentrations can be achieved, but requires appropriate attention to the accuracy of blood sampling and dosing. For this purpose, a special program, i.e., more than ordinary attention to drug therapy, is needed.
Assuntos
Computadores , Gentamicinas/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Gentamicinas/farmacocinética , Meia-Vida , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In vitro models have shown that metabolites of ethanol (acetaldehyde and lactate) stimulate collagen synthesis, thereby, suggesting that they may be important as fibrogenic mediators. The relevance of these findings for fibrogenesis in the human liver in vivo, however, has not as yet been demonstrated. Serum markers for collagen (PIIINP, using radioimmunoassays employing polyclonal antibodies and Fab-fragments (PIIINP-Fab), respectively) and basement membrane (laminin) metabolism were therefore investigated in 25 alcoholic cirrhotics (Pugh-Score: 6.7 +/- 1.9 S.D.) and in 19 comparable nonalcoholic cirrhotics (Pugh-Score: 6.3 +/- 1.5, n.s.) with only slight evidence for inflammation: GOT 28 +/- 22 vs. 24 +/- 21 U/l; GPT 24 +/- 23 vs. 31 +/- 28 U/l; gamma-globulins 24 +/- 8 vs. 22 +/- 5%, respectively (all n.s.). Severity of the disease was assessed by quantitative liver function tests. Levels of PIIINP, PIIINP-Fab and laminin measured by RIA were 21 +/- 19 micrograms/l, 90 +/- 42 micrograms/l and 2.5 +/- 0.8 U/ml in alcoholic cirrhosis and 10 +/- 6 micrograms/l, 61 +/- 10 micrograms/l and 1.9 +/- 0.4 U/ml in nonalcoholic cirrhosis, respectively (all p less than 0.01). Differences on PIIINP and PIIINP-Fab remained significant even after accurate matching for galactose elimination capacity, aminopyrine breath test and hepatic sorbitol clearance. Laminin levels were higher in alcoholic cirrhosis only after matching for the hepatic sorbitol clearance (p less than 0.01). The higher levels of serum markers for collagen and basement membrane metabolism in alcoholic vs. nonalcoholic patients with cirrhosis at equal severity of the disease and with only minimal signs of inflammation may be the clinical reflection of a specific fibrogenic effect of ethanol metabolites.
Assuntos
Laminina/sangue , Cirrose Hepática Alcoólica/sangue , Cirrose Hepática/sangue , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Adulto , Idoso , Biomarcadores/sangue , Feminino , Galactose/farmacocinética , Humanos , Cirrose Hepática/fisiopatologia , Cirrose Hepática Alcoólica/fisiopatologia , Masculino , Taxa de Depuração Metabólica/fisiologia , Pessoa de Meia-Idade , Radioimunoensaio , Índice de Gravidade de Doença , Sorbitol/farmacocinéticaRESUMO
In an exploratory study the 24-h urinary excretion pattern of caffeine and 14 of its major metabolites was studied in 32 volunteers (adults, adolescents and children), 14 patients either with end stage renal disease or liver cirrhosis, 7 heavy smokers and 27 patients on therapy with cimetidine, allopurinol, theophylline or phenytoin. Caffeine and its metabolites were quantified by UV-absorption after liquid/liquid-extraction and HPLC-separation, which ensured proper analysis of 1-methyluric acid. In adults the renal excretion of caffeine derivatives corresponded to an intake of 509 mg caffeine/day, with 1-methyluric acid as the predominant metabolite. About 69% of caffeine was degraded by the paraxanthine pathway, and theobromine- (19%) and the theophylline pathway (14%) were less important. The ratio of paraxanthine formation to urinary caffeine concentration (= clearance equivalent) was about 2.2 ml.min-1.kg-1 in adults, and the corresponding ratios for theophylline and theobromine were 0.43 ml.min-1.kg-1 and 0.59 ml.min-1.kg-1, respectively. As expected, caffeine degradation was impaired in patients with cirrhosis and was increased in persons who smoked heavily or who were on phenytoin therapy. The results document the possibility of noninvasively investigating gross differences in caffeine disposition by analysis of the urinary pattern of its metabolites.
Assuntos
Cafeína/urina , Falência Renal Crônica/urina , Cirrose Hepática/urina , Adolescente , Adulto , Fatores Etários , Alopurinol/farmacologia , Cafeína/análogos & derivados , Cafeína/antagonistas & inibidores , Criança , Cimetidina/farmacologia , Interações Medicamentosas , Feminino , Humanos , Masculino , Fenitoína/farmacologia , Fumar , Teofilina/farmacologiaRESUMO
Unconjugated, mono- and diconjugated bilirubin levels were determined in serum soon after birth, and followed up for several days. Fourteen preterm neonates were studied with a gestational age below 33 weeks (n = 7) or between 34 and 37 weeks (n = 7), respectively, as well as 19 full-term newborns either untreated (n = 9) or treated by phototherapy (n = 10). Bilirubin and its derivatives were analysed by alkaline methanolysis and spectrometry after separation by thin-layer chromatography. In normal full-term neonates total and unconjugated bilirubin reached peak levels at days 2-4. Thereafter, a decline of 11% per day was detectable. Monoconjugates in serum amounted to 3.1 +/- 1.1% of total pigment and remained at that level. The relative amount of diconjugates increased from 0.55 +/- 0.25% (2-4th postnatal day) to 1.62 +/- 0.99% (9-13th day of life). The rapid decline of unconjugated bilirubin paralleled by an increase of diconjugates are an expression of the maturation process for bilirubin conjugation. The premature neonates with less than 33 weeks gestation exhibited an increase of unconjugated serum bilirubin up to the 4-5th postnatal day, the decline thereafter amounted 2% per day. The fraction of 2.3 +/- 1.1% monoconjugates was small and exhibited only a moderate increase in the follow up. In contrast diconjugates were undetectable or very low and remained at this level. These results suggest the presence of a more severe immaturity as well as a slower maturation process of bilirubin conjugation in preterm newborns.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Bilirrubina/sangue , Recém-Nascido/sangue , Idade Gestacional , Humanos , Hiperbilirrubinemia/sangue , Hiperbilirrubinemia/etiologia , Recém-Nascido Prematuro/sangue , Valores de ReferênciaRESUMO
Our laboratory has previously reported that progestins stimulate growth of the human breast cancer cell line T47D. In an attempt to probe further into this stimulation, we are investigating progestin effects on thymidine kinase (EC 2.7.1.21), an enzyme known to be involved in growth regulation. This report relates our finding that progestins stimulate thymidine kinase activity, at physiological progestin concentrations, in a dose-responsive manner. Estradiol-17 beta also stimulates, but testosterone, hydrocortisone and aldosterone do not. The antiprogestin RU486 inhibits progestin stimulation, but also stimulates on its own. Maximal by 24 h, the progestin stimulation then falls off with time. Experiments with actinomycin D and cycloheximide suggest that the thymidine kinase stimulation depends on new RNA and protein synthesis. These data shed further light on progestin stimulation of the growth of human breast cancer. To our knowledge, this is the first report of progestin stimulation of thymidine kinase in human breast cancer cells.
Assuntos
Neoplasias da Mama/enzimologia , Progestinas/farmacologia , Timidina Quinase/metabolismo , Neoplasias da Mama/patologia , Divisão Celular/efeitos dos fármacos , Dactinomicina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Técnicas In Vitro , Mifepristona/farmacologia , Promegestona/farmacologia , Fatores de Tempo , Células Tumorais CultivadasRESUMO
In ten healthy, male subjects the acute effect of pentoxifylline (a methylxanthine derivative) on liver plasma flow was investigated by the extrarenal sorbitol clearance method and on cardiac output by impedance cardiography. On the placebo day liver plasma flow decreased within 4 h from 769 to 683 ml.min-1 (P less than 0.05) and on the pentoxifylline day (300 mg i.v.) it increased from 764 to 801 ml.min-1 (NS). At the end of the experiment the difference between the groups was also significant (P less than 0.05). There was no significant change in cardiac output, blood pressure or heart rate and individual changes in those values were not correlated with liver plasma flow. There was no correlation either between the plasma concentrations of pentoxifylline or its metabolites and the changes in liver plasma flow. It is concluded that, relative to the spontaneous decrease in liver plasma flow at rest on the placebo day, pentoxifylline increased splanchnic perfusion independent of any change in cardiac output.
Assuntos
Circulação Hepática/efeitos dos fármacos , Pentoxifilina/farmacologia , Adulto , Pressão Sanguínea/efeitos dos fármacos , Débito Cardíaco/efeitos dos fármacos , Método Duplo-Cego , Frequência Cardíaca/efeitos dos fármacos , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pentoxifilina/administração & dosagem , Pentoxifilina/urina , Sorbitol/metabolismoRESUMO
Ursodeoxycholic acid treatment of patients with primary biliary cirrhosis may lead to relief of pruritus and improvement of biochemical liver tests. The changes in serum and urinary bile acids induced by ursodeoxycholic acid treatment were studied. After 29 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (750 to 1,000 mg/day) for 6 to 12 mo because of an increase in ursodeoxycholic acid, total plasma bile acids increased from 30.5 +/- 6 mumol/L (mean +/- S.E.M.) to 52.7 +/- 11.7 mumol/L (p less than 0.01). The increase in total plasma bile acids correlated significantly with concentrations of plasma bile acid before treatment (p less than 0.01). The concentrations of endogenous bile acids decreased, mainly because of a decrease of cholic acid. During treatment, glycine conjugation increased and taurine conjugation decreased, whereas sulfation and glucuronidation of bile acids were unchanged. In 10 patients with primary biliary cirrhosis in stages III and IV, urinary excretion of bile acids was also studied. After treatment, ursodeoxycholic acid and its 3-beta isomer and C-1-hydroxylated and C-6-hydroxylated derivatives were also excreted. During treatment, urinary excretion of endogenous bile acids decreased. The increase of ursodeoxycholic acid and the decrease of endogenous bile acids may both be related to the improvement of biochemical liver tests in precirrhotic stages of the disease. In cirrhosis, endogenous bile acids in plasma remained high and changes in liver tests were small.
Assuntos
Ácidos e Sais Biliares/metabolismo , Ácido Desoxicólico/análogos & derivados , Cirrose Hepática Biliar/tratamento farmacológico , Ácido Ursodesoxicólico/uso terapêutico , Ácidos e Sais Biliares/análise , Cromatografia Gasosa , Avaliação de Medicamentos , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Cirrose Hepática Biliar/classificação , Cirrose Hepática Biliar/metabolismo , Ácido Ursodesoxicólico/análise , Ácido Ursodesoxicólico/farmacocinéticaRESUMO
Unconjugated and mono- and diconjugated bilirubin was determined by alkaline methanolysis and thin-layer chromatography in serum from 16 pediatric patients with homozygous beta-thalassemia (aged 1-23 years), in 14 age-matched controls, and in 26 healthy adults. Total bilirubin amounted to 21 +/- 20 mumol/L in patients with thalassemia compared with 7 +/- 4 mumol/L in healthy children and 11 +/- 3 mumol/L in healthy adults. The fractions of bilirubin conjugates in the various groups were 8 +/- 4% (patients with thalassemia), 18 +/- 5% (age-matched controls; p less than 0.001), and 16 +/- 5% (healthy adults; p less than 0.001). The low fraction of bilirubin conjugates in patients with thalassemia showed no correlation to any other physical or laboratory finding. It is concluded that subnormal values of bilirubin conjugates in thalassemia indicate defective bilirubin conjugation.
Assuntos
Bilirrubina/sangue , Icterícia Neonatal/sangue , Talassemia/sangue , Adolescente , Adulto , Bilirrubina/análise , Bilirrubina/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Icterícia Neonatal/complicações , Masculino , Valores de Referência , Talassemia/complicaçõesRESUMO
Nine patients with external ventriculostomy and suffering from hydrocephalus, due to non-inflammatory central nervous system diseases, were given ciprofloxacin (200 mg twice daily iv). Ciprofloxacin concentrations in serum and CSF were measured by HPLC. Single-dose pharmacokinetics were determined in three patients, and 60 and 600 min post-dose levels after repeated administration in six patients. CSF concentrations were maximal 60-120 min after the end of the infusion. The CSF elimination half-life was 260-430 min compared with 145-170 in serum. Post-dose levels at 60 min ranged from 0.042 to 0.223 mg/l (median = 0.110). Repeated administration did not lead to substantial increases in serum and CSF concentrations. With respect to MIC90 values reported for bacteria involved in CNS infections, the CSF concentrations of ciprofloxacin obtained under our experimental conditions would be considered subtherapeutic. Thus ciprofloxacin therapy of CNS infections may be inadequate when only minor impairment of the blood-CSF barrier exists.
Assuntos
Ciprofloxacina/líquido cefalorraquidiano , Meninges/fisiologia , Adulto , Cromatografia Líquida de Alta Pressão , Ciprofloxacina/farmacocinética , Ciprofloxacina/uso terapêutico , Feminino , Meia-Vida , Humanos , Hidrocefalia/cirurgia , Masculino , Pessoa de Meia-Idade , Infecção da Ferida Cirúrgica/prevenção & controle , VentriculostomiaRESUMO
In order to clarify the relative contribution of the liver to the short term disposition of propofol, hepatic blood flow was measured during induction of anaesthesia with an i.v. bolus dose of propofol 2 mg kg-1. Total clearance of the drug was 2390 (SD 340) ml min-1, hepatic extraction 82% and hepatic clearance 1060 (260) ml min-1. During the 60-min period of observation, hepatic extraction of propofol increased from 79% to 92%. It is concluded that, within 1 h, only 44% of the administered dose is removed by the liver. Consequently, drug accumulation may occur with repeated dosing or infusion of propofol. The increase in extraction results presumably from slow release of propofol from the soy-bean emulsion.