At 36.3 minutes, propofol (ip; 40 mg/kg) caused the sedation to fully subside. When measured by ECT, there is residual analgesia, but when measured by insect heat, there is no residual antinociceptive impact [1].

Absorption, Distribution and Excretion
Rapid - time to onset of unconsciousness is 15-30 seconds, due to rapid distribution from plasma to the CNS. Distribution is so rapid that peak plasma concentrations cannot be readily measured. Duration of action is 5-10 minutes.
It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney.
60 L/kg [healthy adults]
23 - 50 mL/kg/min
1.6 - 3.4 L/min [70 Kg adults]
The initial apparent volume of distribution is 13 to 76 L/kg.
Propofol is rapidly and extensively distributed in the body. It crosses the blood-brain barrier quickly, and its short duration of action is due to rapid redistribution from the CNS to other tissues, high metabolic clearance and high lipophilicity.
Approximately 70% of a dose is excreted in the urine within 24 hours after administration, and 90% is excreted within 5 days. Clearance of propofol ranges from 1.6 to 3.4 liters per minute in healthy 70 kg patients. As the age of the patient increases, total clearance of propofol may decrease. Clearance rates of 1.4 to 2.2 liters per minute in patients 18 to 35 years of age have been reported, in contrast to clearance rates of 1.0 to 1.8 liters per minute in patients 65 to 80 years of age.
The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.
An iv dose of 14C-propofol (0.47 mg/kg) administered to 6 male volunteers was rapidly eliminated with 88% recovered in the urine in 5 days and <2% in feces. The dose was cleared by metabolism with <0.3% excreted unchanged. The major metabolites were the glucuronic acid conjugate of propofol and the glucuronic acid and sulfate conjugates of its hydroxylated derivative, 2,6-diisopropyl-1,4-quinol. Propofol glucuronide accounted for about 53% of the urinary radioactivity and was the major metabolite in plasma from 30 min post dose. The blood concentration of propofol declined in a biphasic manner from a maximum mean value of 0.44 ug/ml, 2 min after injection. The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects. A proportion of the dose was cleared slowly, probably due to slow release from less well perfused tissues. Propofol accounted for 94% of the total blood radioactivity at 2 min but only about 6% from 3 to 8 hr post dose. Propofol has a volume of distribution equivalent to about 3 to 4 times body weight, and a mean total body clearance of 2.2 l/min.

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Metabolism / Metabolites
Hepatically metabolized mainly by glucuronidation at the C1-hydroxyl. Hydroxylation of the benzene ring to 4-hydroxypropofol may also occur via CYP2B6 and 2C9 with subsequent conjugation to sulfuric and/or glucuronic acid. Hydroxypropofol has approximately 1/3 of hypnotic activity of propofol.
Hepatic; rapidly undergoes glucuronide conjugation to inactive metabolites. An unidentified route of extrahepatic metabolism may also exist, suggested by the fact that propofol clearance exceeds estimated hepatic blood flow.
To determine the cytochrome P450 (CYP) isoforms involved in the oxidation of propofol by human liver microsomes. The rate constant calculated from the disappearance of propofol in an incubation mixture with human liver microsomes and recombinant human CYP isoforms was used as a measure of the rate of metabolism of propofol. The correlation of these rate constants with rates of metabolism of CYP isoform-selective substrates by liver microsomes, the effect of CYP isoform-selective chemical inhibitors and monoclonal antibodies on propofol metabolism by liver microsomes, and its metabolism by recombinant human CYP isoforms were examined. The mean rate constant of propofol metabolism by liver microsomes obtained from 6 individuals was 4.2 (95% confidence intervals 2.7, 5.7) nmol/min/mg protein. The rate constants of propofol by microsomes were significantly correlated with S-mephenytoin N-demethylation, a marker of CYP2B6 (r=0.93, P<0.0001), but not with the metabolic activities of other CYP isoform-selective substrates. Of the chemical inhibitors of CYP isoforms tested, orphenadrine, a CYP2B6 inhibitor, reduced the rate constant of propofol by liver microsomes by 38% (P<0.05), while other CYP isoform-selective inhibitors had no effects. Of the recombinant CYP isoforms screened, CYP2B6 produced the highest rate constant for propofol metabolism (197 nmol/min/nmol P450). An antibody against CYP2B6 inhibited the disappearance of propofol in liver microsomes by 74% /and SRP: reduced in vitro metabolism by blocking CYP 2B6/. Antibodies raised against other CYP isoforms had no effect on the metabolism of propofol. CYP2B6 is predominantly involved in the oxidation of propofol by human liver microsomes.
Propofol has known human metabolites that include 4-hydroxy-propofol and (2S,3S,4S,5R)-6-[2,6-Di(propan-2-yl)phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid.
Propofol is rapidly distributed into peripheral tissues after absorption. It is highly protein bound in vivo and is metabolised by conjugation in the liver. Propofol is metabolized mainly by glucuronidation by uridine diphosphate-glucuronosyltransferases (UGTs) and by hydroxylation by CYP2B6 and CYP2C enzymes. The enzymes SULT1A1 and NQO1 participate in later steps in propofol metabolism. An unidentified route of extrahepatic metabolism may also exist, suggested by the fact that propofol clearance exceeds estimated hepatic blood flow. (L1002, A600, A304). Propofol is hepatically metabolized mainly by glucuronidation at the C1-hydroxyl. Hydroxylation of the benzene ring to 4-hydroxypropofol may also occur via CYP2B6 and 2C9 with subsequent conjugation to sulfuric and/or glucuronic acid. Hydroxypropofol has approximately 1/3 of hypnotic activity of propofol.
Route of Elimination: It is chiefly eliminated by hepatic conjugation to inactive metabolites which are excreted by the kidney.
Half Life: Initial distribution phase t_1/2α=1.8-9.5 minutes. Second redistirubtion phase t_1/2β=21-70 minutes. Terminal elimination phase t_1/2γ=1.5-31 hours.

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Biological Half-Life
Initial distribution phase t_1/2α=1.8-9.5 minutes. Second redistirubtion phase t_1/2β=21-70 minutes. Terminal elimination phase t_1/2γ=1.5-31 hours.
Terminal elimination half-life is 3 to 12 hours; prolonged administration may result in longer duration.
...The first-stage elimination half-life (t1/2 beta) of propofol /SRP: administered mixed with lidocaine/ in children was shorter (mean 9.3 +/- 3.8 (s.d.) min) than the values found in adults. This pharmacokinetic alteration may have clinical significance following repeated administration or continuous infusion of propofol.
An intravenous dose of 14C-propofol (0.47 mg/kg) /was/ administered to six male volunteers... . ...The half-lives of the first and second exponential phases, mean values 5 min and 97 min respectively, varied widely among subjects.

Hepatotoxicity
Liver test abnormalities are not common among patients during or after propofol anesthesia when given for a few hours. Indeed, propofol can be used safely in patients with cirrhosis and may be the preferred anesthetic agent in patients with minimal hepatic encephalopathy. However, isolated case reports of hepatitis arising within days or weeks after propofol anesthesia for minor procedures have been published. The pattern of serum enzyme elevations was usually hepatocellular and some instances were accompanied by jaundice and prolongation of prothrombin time activity (Case 1). Immunoallergic features and autoantibodies during the liver injury were absent. In most published instances, other diagnoses such as ischemic hepatitis and hepatitis C were not completely excluded.
Prolonged infusions of propofol can result in a distinctive clinical syndrome known as the propofol infusion syndrome. It is marked by combinations of cardiac bradyarrhythmias, metabolic acidosis, rhabdomyolysis, hyperlipidemia, renal insufficiency and death from cardiovascular collapse. The syndrome generally arises after 2 to 3 days of sedation in association with use of higher doses of propofol (>5 mg/kg/hour) and may be more common in children than adults. Early termination of the propofol infusion can result in reversal of the syndrome, but the mortality rate in published series has been greater than 50%. On autopsy, patients with the propofol infusion syndrome may have hepatic microvesicular steatosis, explaining the lactic acidosis that frequently accompanies the muscle and heart abnormalities. However, jaundice and marked elevations in typical liver associated enzymes in this syndrome are uncommon. In some instances, both the urine and the liver have been described as being green in color, returning to normal soon after propofol is stopped. A mild form of this syndrome may occur earlier during infusions, as shown by lactic acidosis arising within 2 to 24 hours of starting propofol which is rapidly reversed upon stopping. More than 50 instances of propofol infusion syndrome have been described in the literature with a high mortality rate, although most deaths were due to cardiac involvement. Some instances of propofol infusion syndrome and lactic acidosis have been associated with higher than expected plasma levels of propofol, perhaps due to idiosyncratic differences in pharmacokinetics or miscalculation of administered dose.
Likelihood score: A[H] (well established cause of fatty liver injury when given in high doses over several days as a part of the propofol infusion syndrome) and D (possible rare cause of idiosyncratic, clinically apparent liver injury when given short term in conventional doses).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Amounts of propofol in milk are very small and are not expected to be absorbed by the infant. Although one expert panel recommends withholding nursing for an unspecified time after propofol administration, most recommend that breastfeeding can be resumed as soon as the mother has recovered sufficiently from general anesthesia to nurse and that discarding milk is unnecessary. When a combination of anesthetic agents is used for a procedure, follow the recommendations for the most problematic medication used during the procedure. General anesthesia for cesarean section using propofol as a component for induction may delay the onset of lactation. In one study, breastfeeding before general anesthesia induction reduced requirements of propofol and sevoflurane compared to those of nursing mothers whose breastfeeding was withheld or nonnursing women. Case reports have noted blue-green or green discoloration of breastmilk after nursing mothers received propofol.
◉ Effects in Breastfed Infants
Four mothers who were breastfeeding their infants received propofol as part of their general anesthesia for surgical procedures. All patients also received intravenous remifentanil and rocuronium, and inhaled xenon as part of the anesthesia. They were given doses of propofol that targeted a serum concentration of 6.5 mcg/L for induction and stopped as xenon anesthesia was started. Operation times ranged from 35 to 45 minutes. Individual infants were first breastfed as follows: 1.5 hours, 2.8 hours, 4.6 hours, and 5 hours after extubation. No signs of sedation were observed in any of the infants after their first feeding or at home after discharge.
◉ Effects on Lactation and Breastmilk
Five women who were 6 to 15 weeks postpartum were given single doses of 2 mg of midazolam and 2.5 mg/kg of propofol intravenously before undergoing general anesthesia. The women's milk output following the surgical procedure was less than half of the normal milk output of nursing mothers. The authors speculated that milk volume might be reduced postoperatively because of perioperative fluid restriction and volume losses, as well as stress-induced inhibition of milk production.
A woman underwent emergency laparoscopic surgery using propofol as well as fentanyl, remifentanil, mivacurium, and dipyrone during the surgery and metamizole, piritramide, dipyrone, butylscopolamine, and metoclopramide postoperatively. Eight hours postoperatively, her milk turned bluish green, then green. Both propofol and metoclopramide have caused green urine. Thirty hours after the milk color change, propofol but not metoclopramide, was detected in milk.
A randomized study compared the effects of cesarean section using general anesthesia, spinal anesthesia, or epidural anesthesia, to normal vaginal delivery on serum prolactin and oxytocin as well as time to initiation of lactation. General anesthesia was performed using propofol 2 mg/kg and rocuronium 0.6 mg/kg for induction, followed by sevoflurane and rocuronium 0.15 mg/kg as needed. Fentanyl 1 to 1.5 mcg/kg was administered after delivery. Patients in the general anesthesia group (n = 21) had higher post-procedure prolactin levels and a longer mean time to lactation initiation (25 hours) than in the other groups (10.8 to 11.8 hours). Postpartum oxytocin levels in the nonmedicated vaginal delivery group were higher than in the general and spinal anesthesia groups.
A randomized, double-blind study compared the effects of intravenous propofol 0.25 mg/kg, ketamine 0.25 mg/kg, ketamine 25 mg plus propofol 25 mg, and saline placebo for pain control in mothers post-cesarean section in mothers post-cesarean section. A single dose was given immediately after clamping of the umbilical cord. The time to the first breastfeeding was 58 minutes in those who received placebo, 42.6 minutes with propofol and 25.8 minutes with propofol plus ketamine. The time was significantly shorter than the other groups with the combination.
A retrospective study of women in a Turkish hospital who underwent elective cesarean section deliveries compared women who received bupivacaine spinal anesthesia (n = 170) to women who received general anesthesia (n = 78) with propofol for induction, sevoflurane for maintenance and fentanyl after delivery. No differences in breastfeeding rates were seen between the groups at 1 hour and 24 hours postpartum. However, at 6 months postpartum, 67% of women in the general anesthesia group were still breastfeeding compared to 81% in the spinal anesthesia group, which was a statistically significant difference.]
A woman nursing an 8-month-old infant 6 to 8 times daily was admitted to the hospital for an appendectomy. During the procedure she received cefazolin, granisetron, ketorolac, rocuronium, succinylcholine, and sufentanil. The patient also received 2 boluses of intravenous propofol of 150 mg followed shortly thereafter by a 50 mg dose. Postoperatively, she was receiving acetaminophen, cefazolin, ibuprofen, and pantoprazole, as well as oxycodone and dimenhydrinate as needed. Twenty-two hours after the procedure, the mother extracted milk for the first time and noted it to be light green in color. Analysis of the green milk using a nonvalidated assay detected no propofol. The green color faded and was absent by postoperative day 4 when she resumed breastfeeding. The authors judged that the green color was possibly caused by propofol or one of its metabolites.
A pregnant woman had an emergency cesarean section delivery in her 24th week of gestation. During the procedure she received 200 mg of propofol as well as cefazolin and acetaminophen after delivery. The first milk expressed by the mother at 12 hours after the procedure was dark green. At 30 hours after the procedure is was light green and returned to a normal color by hour 48.

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Protein Binding
95 to 99%, primarily to serum albumin and hemoglobin

[1]. Antinociceptive Properties of Propofol: Involvement of Spinal Cord Gamma-Aminobutyric acid(A) Receptors. J Pharmacol Exp Ther . 1997 Sep;282(3):1181-6.

Propofol is a phenol resulting from the formal substitution of the hydrogen at the 2 position of 1,3-diisopropylbenzene by a hydroxy group. It has a role as an intravenous anaesthetic, a sedative, a radical scavenger, an antiemetic and an anticonvulsant.
Propofol is an intravenous anaesthetic agent used for induction and maintenance of general anaesthesia. IV administration of propfol is used to induce unconsciousness after which anaesthesia may be maintained using a combination of medications. Recovery from propofol-induced anaesthesia is generally rapid and associated with less frequent side effects (e.g. drowsiness, nausea, vomiting) than with thiopental, methohexital, and etomidate. Propofol may be used prior to diagnostic procedures requiring anaesthesia, in the management of refractory status epilepticus, and for induction and/or maintenance of anaesthesia prior to and during surgeries.
Propofol is a General Anesthetic. The physiologic effect of propofol is by means of General Anesthesia.
Propofol is the mostly commonly used parenteral anesthetic agent in the United States, extensively used for minor and outpatient surgical procedures because of its rapid onset and reversal of action, and in intensive care units (ICUs) for maintenance of coma. Propofol has been associated with rare instances of idiosyncratic acute liver injury; in addition, prolonged high dose propofol therapy can cause the “Propofol infusion syndrome” which is marked by bradyarrhythmias, metabolic acidosis, rhabdomyolysis, hyperlipidemia and an enlarged or fatty liver.
Propofol is a hypnotic alkylphenol derivative. Formulated for intravenous induction of sedation and hypnosis during anesthesia, propofol facilitates inhibitory neurotransmission mediated by gamma-aminobutyric acid (GABA). This agent is associated with minimal respiratory depression and has a short half-life with a duration of action of 2 to 10 minutes.
Propofol is an intravenous anaesthetic agent used for induction and maintenance of general anaesthesia. IV administration of propfol is used to induce unconsciousness after which anaesthesia may be maintained using a combination of medications. Recovery from propofol-induced anaesthesia is generally rapid and associated with less frequent side effects (e.g. drowsiness, nausea, vomiting) than with thiopental, methohexital, and etomidate. Propofol may be used prior to diagnostic procedures requiring anaesthesia, in the management of refractory status epilepticus, and for induction and/or maintenance of anaesthesia prior to and during surgeries.
An intravenous anesthetic agent which has the advantage of a very rapid onset after infusion or bolus injection plus a very short recovery period of a couple of minutes. (From Smith and Reynard, Textbook of Pharmacology, 1992, 1st ed, p206). Propofol has been used as ANTICONVULSANTS and ANTIEMETICS.
See also: Fospropofol Disodium (is active moiety of); Propofol Hemisuccinate (is active moiety of).

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Drug Indication
Used for induction and/or maintenance of anaesthesia and for management of refractory status epilepticus.
FDA Label

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Mechanism of Action
The action of propofol involves a positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A receptors.

C12H18O

178.27

178.135

2078-54-8

Propofol-d18;1189467-93-3;Propofol-d17;1261393-54-7

4943

Light yellow to yellow <18°C powder,>18°C liquid

0.9±0.1 g/cm3

256.0±0.0 °C at 760 mmHg

18 °C(lit.)

107.5±7.2 °C

0.0±0.5 mmHg at 25°C

1.513

4.16

1

1

2

13

135

0

O([H])C1C(=C([H])C([H])=C([H])C=1C([H])(C([H])([H])[H])C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])[H]

OLBCVFGFOZPWHH-UHFFFAOYSA-N

InChI=1S/C12H18O/c1-8(2)10-6-5-7-11(9(3)4)12(10)13/h5-9,13H,1-4H3

2,6-di(propan-2-yl)phenol

FreseniusICI 35868 ICI-35,868Fresofol ICI 35,868 ICI-35868Diprivan 2,6-DIISOPROPYLPHENOL Propofol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~560.95 mM)
H2O : ~0.5 mg/mL (~2.80 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (14.02 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (14.02 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (14.02 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 1 mg/mL (5.61 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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Solubility in Formulation 5: 2.1 mg/mL (11.78 mM) in Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 6: 10 mg/mL (56.09 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)