Propofol Metabolism Research Articles

Functional significance of CYP2B6 gene rare allelic variants identified in Japanese individuals

Cytochrome P450 2B6 (CYP2B6) catalyzes the metabolism of many drugs, including efavirenz and propofol. Genetic polymorphisms in CYP2B6 alter its enzymatic activity and substantially affect its pharmacokinetics. High-frequency variants, such as CYP2B6*6, are associated with the risk of developing side effects due to reduced CYP2B6 activity. However, the impact of rare alterations on enzyme function remains unknown, and some of these variants may significantly decrease the CYP2B6 activity. Therefore, in this study, we evaluated in vitro the functional alterations in 29 missense variants of the CYP2B6 gene identified in 8,380 Japanese individuals. Wild-type CYP2B6 and 29 rare CYP2B6 variants were transiently expressed in mammalian cells. The expression levels of variant CYP2B6 proteins in the microsomal fractions extracted from 293FT cells were assessed using western blotting and reduced-carbon monoxide difference spectroscopy, and a specific peak at 450 nm was detected in the wild-type and 19 variants. Furthermore, kinetic parameters were determined by assaying the reactions with efavirenz and propofol and quantifying the metabolite concentrations. We found that 12 variants had significantly lower or abolished enzymatic activity with both the substrates. In silico three-dimensional docking and molecular-dynamics simulations suggested that these functional changes were due to conformational changes in essential regions, such as the heme-binding site and ligand channels involved in transporting substrates to the active site. These findings have implications for predicting the plasma concentrations of CYP2B6 substrates and controlling their side effects.

Propofol-induced postoperative unconsciousness in hepatocellular carcinoma

Although propofol is a commonly used medication for inducing general anaesthesia, it is not without side effects. In this case report, we present a patient with hepatocellular carcinoma who experienced postoperative unconsciousness following general anaesthesia induction using propofol. While this is a rare occurrence, it underscores the importance of remaining vigilant and understanding propofol’s pharmacokinetic properties. The drug can be redistributed from fat tissues into the systemic circulation, resulting in delayed recovery and potential adverse effects. We also discuss the possible impact of disease interactions, particularly hepatic impairment with possible CYP450 deficiency, on propofol metabolism. We stress the necessity of closely monitoring patients during anaesthesia induction and maintenance.

Altitude effect on Propofol Pharmacokinetics in Rats.

Propofol is an intravenous agent for clinical anesthesia. As the influence of the hypobaric-hypoxic environment (Qinghai-Tibetan region, altitude: 2800-4300 m, PaO2: 15.1-12.4 kPa) on the metabolism of Propofol is complex, the research results on the metabolic characteristics of Propofol in high-altitude areas remain unclear. This study aimed to investigate the pharmacokinetic characteristics of Propofol in a high-altitude hypoxic environment using animal experiments. Rats were randomly divided into three groups: high-altitude, medium-altitude, and plain groups. The time of disappearance and recovery of the rat righting reflex was recorded as the time of anesthesia induction and awakening, respectively. The plasma concentration of Propofol was determined by gas chromatography-mass spectrometry. A pharmacokinetic analysis software was used to analyze the blood-drug concentrations and obtain the pharmacokinetic parameters. We observed that when Propofol anesthetizes rats, the anesthesia induction time was shortened, and the recovery time was prolonged with increased altitude. Compared with the plain group, the clearance of Propofol decreased, whereas the half-life, area under the concentration-time curve, peak plasma concentration, and average residence time extension increased. The pharmacokinetic characteristics of Propofol are significantly altered in high-altitude hypoxic environments.

Effects of CYP2B6 Genetic Variants on the Propofol Dose and Response among Jordanian Arabic Patients Undergoing General Anesthesia.

Propofol is the most commonly used general anesthetic drug in many countries, including Jordan. However, there is a wide variation in the propofols' dose and response among the patients. Genetic variation in the cytochrome (CYP) 2B6 gene affects propofol metabolism and might affect propofol dose and response. This study aimed to determine the influence of major genetic alleles of the CYP2B6 gene, CYP2B6*2A, *6A, *3, *4A, and *5A, on the required propofol dose and response among Jordanian Arabic patients attending The University of Jordan Hospital. A total of 155 patients were administrated propofol. The propofol response was evaluated by monitoring the time to reach the bispectral index of 60 (BIS60) for every patient. The CYP2B6 genetic variants were genotyped by polymerase chain reaction followed by restriction through specific enzymes for CYP2B6 variants. It is found that patients with variant CYP2B6*2A and *4A alleles required significantly (P < 0.05) lower propofol doses, while patients with variant CYP2B6*6A, *3, and *5A alleles required higher propofol doses in comparison with patients carrying the wild CYP2B6 alleles. Patients with variant CYP2B6*2A and *3 alleles needed a significantly (P < 0.05) shorter while patients with variant CYP2B6*5A allele needed longer time of BIS60 than patients with wild CYP2B6*2A, *3, and *5A alleles. It is concluded that CYP2B6 genetic variants affect propofol dose and can explain, at least partly, the inter-individual variation in the propofol response. Further clinical studies with a larger sample size are needed to confirm the findings of this study.

Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study.

The aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult patients undergoing intravenous sedation. In this prospective clinical study, a total of 124 patients undergoing anaesthesia with propofol, as a single drug, were evaluated when undergoing colonoscopy procedure. Clinical variables were obtained from the patient's anamnesis prior to performing the anaesthetic procedure, in the moment of the patient's loss of consciousness, during the colonoscopy exam (recorded every 5 min) and in the awakening time. Polymorphic genotypes for the rs3745274 and rs1057910 polymorphisms were associated with bispectral index, target-controlled infusion (TCI)/effector concentration of propofol and TCI/plasma concentration of propofol values. Based on multivariate analysis, it was observed that weight, age, surgery time, systolic blood pressure and the rs1057910 polymorphism corresponded to predictive values for the dose of propofol used. Weight (B = 4.807±0.897), age (B = 1.834±0.834) and duration of surgery (B = 8.164±1.624) corresponded to factors associated with increased propofol dose, while systolic blood pressure (B = -1.892±0.679) and the genotypes (AA vs CA) of the single nucleotide polymorphism (SNP) rs1057910 CYPP2C9 gene (B = -74.161±26.820) decreased the total dose of propofol used. We concluded that the rs1057910 and rs3745274 polymorphisms affect the metabolism of propofol in patients exclusively submitted to this drug. Thus, the knowledge of the polymorphic genotypes of the CYPP2C9 and CYB2B6 genes may be predictive of different metabolising phenotypes, suggesting expected behaviours of BIS parameter in the anaesthetic procedure, which contributes to safer monitoring by anaesthesiologists during the clinical intervention.

Effect of CYB2B6 (c.516G>T), CYP2C9 (c.1075A>C) and UGT1A9 (c.98T>C) polymorphisms on propofol pharmacokinetics in patients submitted to colonoscopy: a cohort study

BackgroundThe aim of this study was to investigate the effect of CYB2B6 (c.516G>T, rs3745274), CYP2C9 (c.1075A>C, rs1057910) and UGT1A9 (c.98T>C, rs72551330) polymorphisms on the pharmacokinetics of single-drug propofol in adult...

&lt;p&gt;The Effect of &lt;em&gt;UGT1A9&lt;/em&gt;, &lt;em&gt;CYP2B6&lt;/em&gt; and &lt;em&gt;CYP2C9&lt;/em&gt; Genes Polymorphism on Propofol Pharmacokinetics in Children&lt;/p&gt;

PurposeThis study was conducted to determine the effect of UGT1A9 98T>C, CYP2B6 516G>T and CYP2C9 430C>T genetic polymorphisms on the pharmacokinetics of propofol in children of different sexes and ages who undergone total intravenous anesthesia (ТIVA) and deep sedation during diagnostic and therapeutic procedures.Patients and MethodsThe prospective study included 94 children, ASA I-II status, 1 to 17 years of age, who undergone standard anesthetic protocol for TIVA, which implied the continuous use of propofol. Before the administration of propofol, venous blood was sampled to determine the presence of genetic variations in UGT1A9, CYP2B6 and CYP2C9 gene using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). From each patient included in the study blood samples were taken: 10 mins after the induction of anesthesia, immediately before the discontinuation of the propofol infusion, 10 mins after discontinuation of the propofol infusion and 20 mins after discontinuation of the propofol infusion to determine the pharmacokinetics of the drug in the plasma of the subjects The plasma propofol concentration was determined by HPLC analytical technique.ResultsUGT1A9 genotype is an independent predictor of the propofol concentration in children immediately after the end of the continuous infusion and 10 mins afterwards. In the carriers of the polymorphic UGT1A9 C allele, the propofol distribution constant was higher. The carriers of the polymorphic CYP2B6 T allele received a significantly lower overall and initial dose of propofol. Unlike polymorphism of the UGT1A9 gene, the tested CYP2C9 and CYP2B6 gene polymorphisms are not independent predictors of the pharmacokinetics of propofol.ConclusionFurther investigations of UGT1A9, CYP2B6 and CYP2C9 and other genes that participate in propofol metabolism as well as detailed analyses of the general conditions, administered therapies and associated diseases could explain the large interindividual variability of propofol metabolism in children.

Metabolic Profiles of Propofol and Fospropofol: Clinical and Forensic Interpretative Aspects.

Propofol is an intravenous short-acting anesthetic widely used to induce and maintain general anesthesia and to provide procedural sedation. The potential for propofol dependency and abuse has been recognized, and several cases of accidental overdose and suicide have emerged, mostly among the health professionals. Different studies have demonstrated an unpredictable interindividual variability of propofol pharmacokinetics and pharmacodynamics with forensic and clinical adverse relevant outcomes (e.g., pronounced respiratory and cardiac depression), namely, due to polymorphisms in the UDP-glucuronosyltransferase and cytochrome P450 isoforms and drugs administered concurrently. In this work the pharmacokinetics of propofol and fospropofol with particular focus on metabolic pathways is fully reviewed. It is concluded that knowing the metabolism of propofol may lead to the development of new clues to help further toxicological and clinical interpretations and to reduce serious adverse reactions such as respiratory failure, metabolic acidosis, rhabdomyolysis, cardiac bradyarrhythmias, hypotension and myocardial failure, anaphylaxis, hypertriglyceridemia, renal failure, hepatomegaly, hepatic steatosis, acute pancreatitis, abuse, and death. Particularly, further studies aiming to characterize polymorphic enzymes involved in the metabolic pathway, the development of additional routine forensic toxicological analysis, and the relatively new field of ‘‘omics” technology, namely, metabolomics, can offer more in explaining the unpredictable interindividual variability.

Ring-oxidative biotransformation and drug interactions of propofol in the livers of rats.

Propofol, an intravenous anesthetic agent, is widely used for inducing and maintaining anesthesia during surgical procedures and for sedating intensive care unit patients. In the clinic, rapid elimination is one of the major advantages of propofol. Meanwhile, the biotransformation and drug interactions of propofol in rat livers are still little known. In this study, we evaluated the ring-oxidative metabolism of propofol in phenobarbital-treated rat livers and possible drug interactions. Administration of phenobarbital to male Wistar rats significantly increased levels of hepatic cytochrome P450 (CYP) 2B1/2 and microsomal pentoxyresorufin O-dealkylase (PROD) activity. Analyses by high-performance liquid chromatography and liquid chromatography mass spectroscopy revealed that propofol was metabolized by phenobarbital-treated rat liver microsomes into 4-hydroxypropofol. In comparison, PROD activity and 4-hydroxy-propofol production from propofol metabolism were suppressed by orphenodrine, an inhibitor of CYP2B1/2, and a polyclonal antibody against rat CYP2B1/2 protein. Furthermore, exposure of rats to propofol did not affect the basal or phenobarbital-enhanced levels of hepatic CYP2B1/2 protein. Meanwhile, propofol decreased the dealkylation of pentoxyresorufin by phenobarbital-treated rat liver microsomes in a concentration-dependent manner. Taken together, this study shows that rat hepatic CYP2B1/2 plays a critical role in the ring-oxidative metabolism of propofol into 4-hydroxypropofol, and this anesthetic agent can inhibit CYP2B1/2 activity without affecting protein synthesis.

Impact of CYP2C9 Polymorphism Found in the Chinese Population on the Metabolism of Propofol &lt;i&gt;in Vitro&lt;/i&gt;

The microsomal CYP2C9 alleles involved in the biotransformation of propofol, a widely used anesthetic agent, were investigated in vitro. To examine the enzymatic activity of the CYP2C9 alleles, kinetic parameters for propofol 4-hydroxylation were determined in recombinant human P450s CYP2C9 microsomes from Sf21 insects cells carrying CYP2C9*1 and other variants. Some of the variants showed decreased enzyme activity compared with the wild type, as previously reported. Two variants (CYP2C9*36 and *56) were found substantially to increase intrinsic clearance relative to the wild type variant. Most variants significantly (p<0.05) decreased intrinsic clearance of propofol compared with the wild type, except *11, *47, and *54. This study is the first to report these rare alleles for propofol metabolism, providing fundamental data for further clinical studies on CYP2C9 alleles for propofol metabolism in vivo.

A comparative study of induction characteristics of thiopentone, midazolam and propofol in elderly patients

Background Intravenous anaesthetic agents are used commonly to induce anaesthesia, as induction is usually smoother and more rapid than that associated with most of the inhalation agents. Thiopentone is the most widely used intravenous induction agent in current anaesthetic practice. Propofol (2,6 diisopropyl phenol) is a new rapidly acting intravenous anaesthetic. The rapid redistribution and metabolism of propofol, result in a short elimination half life. Midazolam is an imidazobenzodiazepine with relatively rapid onset of action and high metabolic clearance compared to other benzodiazepine. Objectives This prospective study was carried out to compare the induction characteristics of thiopentone, midazolam and propofol in elderly patients. Methods Ninety adult patients, aged between 60-80 years with ASA grade I &amp;II who were scheduled for general surgery in Bangabandhu Sheikh Mujib Medical University, CMH Dhaka and CMH Saidpur were included in this study. The patients were divided into three groups of thirty each according to a randomization table.The overall performance of the drugs were assessed by recording the following parameters: 1) Pain on injection. 2) Induction time ( The time from start of injection to the loss of eye lash reflex). 3) Coughing 4. Involuntary motor activity. 5. Apnoea (present/absent). 6. Haemodynamic changes (Heart rate and blood pressure at 2 min before injection, after induction and 1min, 3min and 5min after intubation). 7. Recovery time ( From the end of reversal until the patient responded to vocal command(eye opening, tongue protrution). Results The incidence of pain on injection was greater in propofol group(38%), which was statistically significant(p&lt;0.01). The induction time was significantly longer(p&lt;0.001) in the midazolam group. Incidence of excitatory effects was more common in propofol group(p&lt;0.05). Incidence of apnoeic episodes were significantly greater in thiopentone and propofol group than midazolam group(p&lt;0.05). Propofol caused significant decrease in systolic, diastolic and mean arterial pressure at 3 &amp; 5 minutes after intubation(p&lt;0.001).Neither Thiopentone, midazolam nor propofol caused significant change in heart rate. Recovery time in midazolam group was significantly longer(p&lt;0.001). Conclusion Thiopentone is the drug of choice for induction in elderly patients because of rapid induction, recovery and the least effect on arterial pressure. Propofol has no clear advantage over thiopentone and has the additional problem of a significant decrease in blood pressure. Midazolam, although safe, is clearly not the ideal drug for induction in elderly patients because of slow onset of action and delayed recovery. DOI: http://dx.doi.org/10.3329/jbsa.v26i1.19808 Journal of Bangladesh Society of Anaesthesiologists 2013; 26(1): 5-11

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Introduction: Case Report: Drug-induced liver injury is the leading cause of acute liver failure among patients referred for liver transplantation and the most common reason that drugs in development do not obtain approval by the Food and Drug Administration. Propofol is an anesthetic widely used in pediatric and adult populations, and propofol infusion syndrome has been well documented; however, there are very few published case reports implicating propofol infusion in acute liver injury. Five case reports were identified using PubMed: three occurred after gastrointestinal procedures, one after a varicose vein stripping procedure, and one after electroconvulsive shock therapy. We present the first documented case of acute hepatitis resulting from propofol use for induction and post-intubation sedation. We report a case of a 33 year-old hypertensive male who presented with a pontine hemorrhage. During his Intensive Care Unit (ICU) course, this patient was intubated and placed on a propofol infusion for sedation. He developed a transaminitis that resolved when the propofol infusion was stopped. We postulate that propofol was the underlying causative agent in this patient's acute hepatitis. Case Description: A 33 year old hypertensive male without a prior history of liver disease presented with sudden collapse and was found to have a right pontine hemorrhage. He was intubated for airway protection in the Emergency Department (ED) without propofol. On day three of his ICU course, he failed a trial of extubation and was reintubated with propofol 140mg being used for induction but not for post-intubation sedation. On day four, he self-extubated and was again reintubated with propofol 150mg for induction. A propofol infusion was started for sedation at a rate of 5mcg/kg/min. On day six of his stay, the second day of his propofol infusion he was found to have a transaminitis with alanine transaminase (ALT) 656, aspartate aminotransferase (AST) 240 and alkaline phosphatase (ALP) 174. Right upper quadrant ultrasound was unremarkable with normal appearance of the liver in terms of size, configuration and echo content on the same day. The propofol infusion was stopped; the following day his repeat ALT was 482, AST 140 and ALP 133. The patient's ALT, AST and ALP continued to trend down over the following six days to normal levels. Discussion: Inhibition of mitochondrial function has been proposed as a potential mechanism by which propofol may cause accumulation of free fatty acids within hepatocytes, hepatic steatosis and acute liver injury. Genetic studies have identified differences in propofol metabolism and have proposed this as a factor in rare instances of propofol-induced hepatic injury. One case report described the use of drug lymphocyte stimulation testing as a potential tool in identifying patients with propofol induced liver injury. The growing number of case reports documenting hepatic injury after propofol administration may indicate a significant unrecognized clinical burden of disease. A simple screening tool has recently been proposed for propofol infusion syndrome. We submit that a similar screening tool for propofol induced hepatic injury would be valuable to clinicians. Further research is required to delineate the incidence of this syndrome in clinical practice and to develop tools to aid clinicians in the identification of susceptible individuals.

Sex Difference in Formation of Propofol Metabolites: A Replication Study

Women recover faster from propofol anaesthesia and have been described to have a higher incidence of awareness during surgery, compared to men - an effect that may be inherent in sex differences in propofol metabolism. In an observational study, 98 ASA I-II patients treated with continuous propofol infusion were recruited. The associations between sex and CYP2B6 and UGT1A9 polymorphisms with dose- and weight-adjusted area under the total plasma level time curves (AUC) for propofol, and its metabolites propofol glucuronide (PG), 4-hydroxypropofol (OHP) and hydroxyl glucuronide metabolites 4-hydroxypropofol-1-O-β-D-glucuronide (Q1G) and 4-hydroxypropofol-4-O-β-D-glucuronide (Q4G), were analysed. Significantly higher AUC of PG (1.3 times, p=0.03), Q1G (2.9 times, p<0.001), Q4G (2.4 times, p<0.01) and OHP (4.6 times, p=0.01) were found in women (n=53) than in men (n=45) after intravenous infusion of propofol using target-controlled infusion system. There was, however, no significant impact of gene polymorphisms on propofol biotransformation. The results, which are supported by a previous pilot study using a propofol bolus dose, suggest that, compared to men, more rapid propofol metabolism may occur in women - a factor that may contribute to the mentioned differences in the efficacy of propofol anaesthesia between male and female patients.

The effect of hypergravity exposure for two weeks on propofol anesthesia in rats

General anesthesia in space flight is a big challenge for now. To achieve this, understanding the influence of gravitational change on central nervous system (CNS) modulation is required, however it is still unclear. The vestibular system is known to be a highly plastic organ. Previous studies reported that the hypergravity exposure induced plastic alteration of the glutaminergic and GABAergic system via the vestibular system. We hypothesized that hypergravity exposure‐induced CNS modulation might change the effectiveness of anesthetic agent. To clarify this hypothesis, we examined the effect of the intravenous propofol anesthesia in rats reared in 1 G and 3 G environments for 14 days. We measured electroencephalogram (EEG), electrical stimulation‐induced pressor response, propofol metabolism, and GABAA β2/3 subunits in the brain. EEG data showed that the hypnotic effect of propofol (20mg/kg) in 3 G rats was prolonged (43.7 ± 2.9 min) than that in 1 G (26.0 ± 1.0 min) rats. This effect was completely abolished by vestibular lesion (29.7 ± 1.6 min) in 3 G rats. Since there was no difference in propofol metabolism among groups, hypergravity exposure might alter the sensitivity of the propofol via vestibular system.

Evaluation of UGT Protein Interactions in Human Hepatocytes: Effect of siRNA Down Regulation of UGT1A9 and UGT2B7 on Propofol Glucuronidation

Previous experiments performed in recombinant systems that over‐express either a single or multiple UDP‐glucuronosyltranseferase (UGT) isoforms have suggested that protein‐protein interactions occur between the UGTs and may play a significant role in modulating enzyme activity. However, evidence of UGT protein‐protein interactions either in vivo or in more physiologically relevant in vitro systems has yet to be demonstrated. In the current study, we examined oligomerization and its ability to affect glucuronidation in plated human hepatocytes. siRNA down regulation experiments and activity studies were used to examine changes in metabolite formation due to disrupted protein interactions. Selective siRNA down regulation of UGT1A9 or UGT2B7 resulted in significant and selective decreases in their respective mRNA levels. As expected, the metabolism of the UGT1A9 probe substrate propofol decreased with UGT1A9 down regulation. Interestingly, UGT1A9 activity was also diminished when UGT2B7 expression was selectively inhibited, implying potential interactions between the two isoforms. To our knowledge, this represents the first piece of evidence that UGT protein‐protein interactions occur in human hepatocytes and suggests that expression levels of UGT2B7 may directly impact the glucuronidation activity of selective UGT1A9 substrates such as propofol.

Urinary metabolites after intravenous propofol bolus in neonates

In neonates, propofol mainly undergoes hydroxylation to quinol metabolites with only limited glucuronidation. The aim of this study is to search for covariates of neonatal propofol biotransformation based on 24h urine collections. In neonates receiving an intravenous propofol bolus for short procedural sedation, urine was collected during 24h. Urinary propofol metabolites [propofol glucuronide (PG), 1- and 4-quinol glucuronide (QG)] were determined using high-performance liquid chromatography after a dual-step solid phase extraction combined with ultraviolet and fluorescence detection. Propofol metabolites, their contribution to total metabolite elimination and propofol glucuronide/quinol glucuronide (PG/QG) ratio were determined. The impact of continuous [postmenstrual age (PMA), postnatal age (PNA), body weight, propofol dose, creatinaemia] and dichotomous variables [PNA≤7days (yes/no), PNA≥10days (yes/no), hyperbilirubinaemia (yes/no), cardiopathy (yes/no)] on PG/QG ratio and on patients with low (≤10%) vs. high (>10%) urinary PG recovery were examined. Thirty-two neonates were included. Median total propofol metabolite recovery was 40.95 (2.01-129.81)% with PG/QG ratio 0.44 (0.01-5.93). PNA (dichotomous 7days as well as 10days) was a significant covariate of PG/QG ratio. Late PNA more frequently resulted in high urinary PG fraction. Significance was more pronounced with PNA 10days as cut-off point for early neonatal life compared to 7days. Age 10days is pivotal in early life propofol metabolism. This confirms earlier documented propofol clearance studies. This is the first report of the modified quantification assay used to determine urinary propofol metabolites in neonates.

Comparison of GC/MS and LC/MS methods for the analysis of propofol and its metabolites in urine

Gas chromatography–mass spectrometry (GC/MS) and liquid chromatography–mass spectrometry (LC/MS) were compared for their capacity to metabolite identification, sensitivity, and speed of analysis for propofol and its metabolites in urine samples. Acidic hydrolysis, liquid–liquid extraction (LLE), and trimethylsilyl (TMS) derivatization procedures were applied for GC/MS analysis. The LC/MS analysis used a simple sample pretreatment based on centrifugation and dilution. Propofol and four metabolites were successfully analyzed by GC/MS following TMS derivatization. One compound, di-isopropanolphenol was tentatively characterized as a new metabolite observed for the first time in human urine. The TMS derivatization greatly improved the chromatographic properties and detection sensitivity, especially for hydroxylated metabolites. The lower limits of quantitation (LLOQ) of propofol were about 325 and 0.51ng/mL for the GC/MS scan mode and selected ion monitoring (SIM) mode, respectively. In addition, five conjugated propofol metabolites were successfully analyzed by LC–MS/MS in negative ion mode. The detection sensitivity for these conjugated metabolites could be greatly enhanced by the addition of triethylamine to the mobile phase without any loss of LC resolution capacity. The LLOQs of propofol-glucuronide (PG) were about 1.17 and 2.01ng/mL for the LC–MS-selected ion monitoring (SIM) and multiple reaction monitoring (MRM) mode, respectively. Both GC/MS and LC/MS methods sensitively detected nine metabolites of propofol and could be used to provide complementary data for the reasonable propofol metabolism study. Urinary excretion profiles for propofol and its metabolites following administration to human were suggested based on the total ion chromatograms obtained by GC/MS and LC/MS methods, respectively.

The influence of oral VPA on the required dose of propofol for sedation during dental treatment in patients with mental retardation: A prospective observer‐blinded cohort study

In sedation of dental patients with moderate or severe mental retardation, it is difficult to identify the optimum sedation level and to maintain it appropriately. Moreover, many patients have concomitant epilepsy and are medicated with oral antiepileptic drugs (AEDs), which influence the drug-metabolizing enzymes. In particular, valproate (VPA) has been demonstrated to inhibit propofol metabolism in vitro. Therefore, the objective of the present study was to investigate the clinical influence of oral VPA on the required dose of propofol for sedation, with use of a prospective cohort study design. We studied 45 patients with moderate or severe mental retardation who underwent dental treatment under sedation. Propofol was infused, and sedation was maintained at the same level in all patients using a bispectral index (BIS) monitor. After the completion of treatment for the scheduled patients, patients were divided into those with oral VPA treatment (VPA group: 20 patients) and without any oral antiepileptic treatment (control group: 25 patients). The propofol dose required for sedation and times to the recovery of the eyelash reflex and spontaneous eye opening were evaluated. The median required propofol doses in the VPA and control groups were 4.15 (range 1.97-5.88) and 5.67 (2.92-7.17) mg/kg/h, respectively. We observed a statistically significant difference between the two patient groups with respect to median VPA dose (p < 0.01). However, no statistically significant differences were noted in the time until eyelash reflex recovery or spontaneous eye opening between the two groups. The results suggest that oral VPA reduces the dose of propofol required for sedation during dental treatment in patients with moderate or severe mental retardation.

Influence of sex on propofol metabolism, a pilot study: implications for propofol anesthesia

The basis of high intersubject variability of propofol metabolism is unclear. Therefore, we examined the influence of genetic polymorphisms of the key metabolizing enzymes cytochrome P450 2B6 (CYP2B6) and uridine diphosphate (UDP)-glucuronosyltransferase 1A9 (UGT1A9), age, and sex on propofol biotransformation in vitro and in vivo. Plasma concentrations of propofol, 4-hydroxypropofol, and their glucuronides were measured over 20 min in 105 patients after a single intravenous bolus of propofol. Propofol 4-hydroxylation activity, genotypes, and content of CYP2B6 protein in 68 human livers were determined. The common single nucleotide polymorphisms (SNPs) for the CYP2B6 and UGT1A9 genes were analyzed by polymerase chain reaction (PCR). Plasma levels of propofol metabolites showed high interindividual variability (range of coefficient of variation 89-128%). This was supported by in vitro data showing similar variability of propofol 4-hydroxylation in liver microsomes and 1.9-fold higher CYP2B6 protein content in the livers from women. No significant relationships were revealed between the SNPs studied and propofol metabolism. However, patients' sex had a pronounced effect on propofol metabolism. Thus, women had higher amounts of propofol glucuronide (1.25-fold; p = 0.03), 4-hydroxypropofol-1-glucuronide (2.1-fold; p = 0.0009), and 4-hydroxypropofol-4-glucuronide (1.7-fold; p = 0.02) as shown by the weight-corrected area under the time-plasma concentration curve of metabolites. Additionally, the sexual dimorphism in 4-hydroxypropofol glucuronidation was prominent in the 35- to 64-year-old subgroup. No significant effects of CYP2B6 and UGT1A9 SNPs or age on propofol metabolism were revealed in this pilot study, but there was a pronounced effect of sex, a finding that indicates an important factor for the previously described sex difference in systemic clearance of propofol seen.

Increase of propofol requirement after repeated administration for experimental anaesthesia

Increase of propofol requirement after repeated administration for experimental anaesthesia