Propofol Injection - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
Россия
  • Россия
  • Украина

Propofol Injection - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Anesthesia, Sedation
Class: General anesthetics
Form: Intravenous (IV), Powder
Ingredients: Propofol, Soybean Oil, Glycerin, Egg Phospholipids, Oleic Acid, Sodium Hydroxide

Pharmaceutical Information

Drug Substance

Proper Name: Propofol
Chemical Name: 2,6-bis(1-methylethyl)phenol
Code Name:
Molecular Formula: C12H18O
Molecular Mass: 178.27 g/mol
Structural Formula:
Physicochemical Properties: Colourless or very lightly yellow clear liquid. Very soluble in methanol and in ethanol, slightly soluble in cyclohexane and in isopropyl alcohol, very slightly soluble in water, miscible with hexane. pKa of 11.1 in water and a Melting Point of 18 °C.

Detailed Pharmacology

Propofol was administered as a 1% w/v aqueous emulsion containing 10% w/v soya bean oil, 1.2% w/v egg phosphatide and 2.25% w/v glycerol. Control animals received the vehicle. The drug was administered by the intravenous route unless otherwise indicated.

Anaesthetic Activity

Mice

The HD50, i.e., the dose that abolished the righting reflex in 50% of the animals for 30 seconds or more, was 12.8 mg/kg. Induction times were significantly affected by the rate of injection. Namely, they were 4.6 and 12.6 seconds, respectively, after the injection of a 15 mg/kg dose over one or ten seconds. However, the rate of injection did not influence sleeping times or the duration of apnea to a significant degree. To evaluate the effect of repeated bolus injections, propofol was administered at a 25 mg/kg dose, which in previous experiments was shown to induce anaesthesia for approximately 4 minutes. When the mice regained their righting reflex, they were re-injected after an interval of 30 seconds. This procedure was repeated until the animals received a total of 10 injections. Sleeping times increased with subsequent injections.

The mean sleeping time was 4.6 minutes after the first injection and 19.4 minutes after the 8th injection indicating a slight cumulative effect.

Rats

In rats propofol produced a very steep dose-response curve, thus, only a range could be established for the HD50 (5.0 to 7.5 mg/kg). In this species, the anaesthetic effect was sex dependent, female rats having significantly longer sleeping times than male rats. In a separate experiment, utilizing female rats, anaesthesia was induced by a 7.5 - 10 mg/kg bolus dose of propofol and then maintained by the infusion of a 50 mg/kg/h dose. Anaesthesia was maintained for either one or two hours. The experiment established that heart rate and rate of respiration remained stable over the two hour infusion and did not change vis á vis baseline. Recovery times were slightly longer after the two hour infusion but were significantly shorter in propofol-treated rats than in alphaxalone/alphadolone-treated animals.

Cardiovascular and Respiratory Effects

The experiments were conducted in mini-pigs. Propofol was evaluated at a 3.75 mg/kg dose injected over a 30 second interval.

All the changes mentioned were statistically significant. Maximal changes from baseline are indicated in brackets. Mean arterial pressure decreased (107 → 78 mmHg) and was accompanied by reflex tachycardia (105 → 189 beats/min). Rate of respiration became depressed (27.5 → 21.5 breaths/min) and was accompanied by decreased PO2 (94.6 → 79.1 mmHg) and increased PCO2 (40.4 → 44.3 mmHg). Total peripheral resistance decreased (2919 → 1902 dyne. sec. cm-5 ) while cardiac output increased (2.67 → 3.58 L/min). The hypotensive effect of propofol is probably due to reduced peripheral resistance.

Drug Interaction Studies

Preanaesthetic Medications

The experiments were conducted in mice. Diazepam, droperidol, promethazine, atropine, amylobarbital or papaveretum were administered subcutaneously, 30 minutes before the induction of anaesthesia with propofol (18 mg/kg). At the doses tested, only diazepam (2 mg/kg) enhanced significantly the duration of sleep. Recovery times were prolonged significantly byboth diazepam and atropine (1 mg/kg).

Drugs Used in Balanced Anaesthesia

The experiments were conducted in dogs. Anaesthesia was induced by propofol and maintained by halothane. In the first set of experiments, the dogs were premedicated with atropine and fentanyl, while in the second set of experiments premedication was not employed. The following changes were observed in the presence of atropine and fentanyl: the induction doses of propofol were smaller (4.3 versus 7.9 mg/kg) and the concentration of halothane lower (1% versus 2%). However, both tachycardia and apnea occurred. Recovery times were shorter, probably due to the lower dose of propofol.

The Effect of Propofol on Adrenocortical Function

The effect of propofol was compared to that of etomidate on ACTH-stimulated cortisol production in two in vitro models, namely in guinea pig and bovine adrenal cells. Propofol affected cortisol production only at the 10-4M concentration, while etomidate exerted an activity at 10-7M concentration.

In propofol-anaesthetized rats, 5 µg ACTH elicited serum corticosterone levels of 37.2 µg/100 mL while in etomidate-anaesthetized rats, the value was 8.5 µg/100 mL. Since basal corticosterone levels ranged between 5.6 and 10.4 µg/100 mL, ACTH did not elevate corticosterone levels in etomidate-anaesthetized rats. The experiments indicated that propofol is only a very weak inhibitor of adrenal steroidogenesis.

In Vitro Studies

The aim of the experiments was to establish whether or not propofol exerts agonist or antagonist activity at various receptor sites. Only weak antagonist activities were detected at the β1 adrenoceptor, muscarinic cholinergic and 5-HT2 receptor sites. The pA2 values were 5.23, 5.43 and 5.18, respectively. At the same receptor sites the pA2 values for the standards were as follow: propranolol: 8.55, hyoscine: 9.38 and cyproheptadine: 8.2.

Behavioral Studies

The behaviour of mice was observed following the administration of 30, 100 and 300 mg/kg oral doses of propofol. None of the animals were anaesthetized by these oral doses. The lowest dose had no behavioral effects. The mid dose decreased locomotion. The highest dose produced sedation, ptosis, ataxia, slight tremors, hypothermia and decreased rate of respiration.

Miscellaneous Studies

Histamine Release

The administration of propofol, 7.5 mg/kg to dogs was not associated either with elevated plasma histamine levels or with clinical signs indicative of histamine release.

Hypersensitivity

Mini-pigs were anaesthetized with propofol, 2.5 mg/kg on two occasions at one week interval. No reactions, indicative of an anaphylactoid response were seen following the second injection.

Bronchomotor Tone

In the guinea-pig Konzett-Rossler technique, propofol (2.5 mg/kg) was devoid of both bronchoconstrictor and bronchodilator activity. The latter effect was tested against histamine-induced bronchoconstriction.

Blood Coagulation

ADP-induced platelet aggregation was similar in propofol (15 mg/kg) and saline-treated rats. Whole blood clotting times were similar in propofol (15 mg/kg) and saline-treated rats.

Renal Function

In rats, propofol, 15 mg/kg, had little effect on urine volume and urinary potassium and chloride levels. Sodium levels were slightly but significantly decreased (81% of control).

Cat Nictitating Membrane Preparation

Propofol, in a dose-range of 0.5 to 5.0 mg/kg, did not affect the contraction of the nictitating membrane, evoked by preganglionic stimulation of the cervical sympathetic nerve. The study indicates that propofol is devoid of ganglion blocking activity. Furthermore, propofol did not affect the pressor effect of norepinephrine, indicating a lack of effect on adrenoceptors.

Pharmacokinetics

Pharmacokinetic studies were carried out in male and female rats, male and female dogs and female rabbits. In all species, following a single intravenous dose, the pharmacokinetics fit a two-compartment open model with a very rapid distribution phase (t½α: 1.2 - 4.9 min) and a rapid elimination phase (t½β: 15 - 27 min; Table 2). In rats, but not in dogs, a sex difference was observed regarding several pharmacokinetic parameters.

In rats, maximal mean propofol blood concentrations as well as AUC values and propofol blood concentrations at awakening were significantly higher in females. However, elimination half- lives were the same for the two sexes. Both propofol blood concentrations and AUC values increased in a dose-dependent manner. In contrast, waking blood concentrations were independent of the dose. In dogs, the pharmacokinetic parameters were determined either after a bolus injection of propofol (5 and 10 mg/kg) or in an infusion model where an initial bolus dose of 7.5 mg/kg was followed by an infusion at the rate of 0.5 mg/kg/min for 45 minutes (22.5 mg/kg). Steady-state blood concentrations (Css) in the infusion model were achieved within 25 minutes. The elimination half-life was significantly longer following the infusion than after the bolus doses (Table 1). In addition, total body clearance (TBCL) was significantly slower after the infusion (TBCL = 1.0 L/min) than after the 5 mg/kg (TBCL = 1.92 L/min) or 10 mg/kg (TBCL = 2.12 L/min) bolus administrations. Waking propofol concentrations in the dog were ∼ 1 µg/mL.

Table 1: Pharmacokinetic Parameters Following a Single Intravenous Dose of Propofol
Species Dose (mg/kg) Sex Maz propofol blood conc. (µg/mL) AUC (µg.mL min) t½β(min) Sleeping time (min) Waking propofol conc. (µg/mL)
Rat 5 M 0.57 13.7 23 Rats did not sleep
F 2.55 34.4 22
F (pregnant) 2.35 34.8 25
10 M 4.3 48.3 23 6.1 1.7
F 11.3 87.9 18 7.9 2.8
15 M 11.3 97.2 22 9.6 1.0
F 20.8 174.9 27 11.4 3.7
Dog 5 M&F 2.35 40.3 16
10 M&F 4.31 71.4 21
30 (infussion) M&F C55:6.5 33
Rabbit 5 F 260 14.4 15

Distribution

Tissue levels of total radioactivity and propofol were determined in rats following the administration of a 9.7 mg/kg intravenous dose of 14C-propofol. In all tissues assayed, other than fat, the highest concentration of radioactivity were detected five minutes after dosing and decreased thereafter. Maximal concentration in brown fat occurred at 10 minutes and in white fat at 30 and 60 minutes in males and females, respectively. This indicated that the distribution of propofol into fat occurs after five minutes.

Table 2: Concentrations of total radioactivity and propofol in selected tissues of rats 5 minutes after the intravenous administration of 14C-propofol
Tissue Sex Total radioactivity (µg/equivalents/mL) Propofol (µg/mL of g) Propofol - 1% of total radioactivity
Blood M 5.18 1.47 28
F 6.83 3.42 50
Brain M 5.54 5.12 92
F 9.87 9.16 93
Liver M 32.77 1.58 5
F 32.13 15.10 47

Tissue concentrations of total radioactivity were similar in male and female rats, except in the brain where radioactivity was significantly higher in the females (Table 2). The rate of decrease of radioactivity was greatest in the brain; by 30 minutes total radioactivity decreased to 19% and 15% of the 5 minute levels in males and females, respectively. The concentration of propofol in the blood, brain and liver was significantly higher in females. While propofol comprised > 90% of the radioactivity in the brain of both sexes, in the blood and liver propofol concentrations were considerably lower and a sex difference was evident. In the liver, propofol levels were about ten times higher in female rats indicating initial differences in the rate of metabolism between the sexes.

Metabolism and Elimination

14C-propofol (10 mg/kg) was extensively metabolized and rapidly eliminated in the urine and feces of rats and dogs. In the rabbit, excretion occurred almost exclusively in the urine (Table 3).

Table 3: The excretion of 14C-propofol
% dose
Species Sex Urine Feces Bile Total Recovery
Rat M 60 31 92a
F 75 15 91a
F (pregnant) 77 16 95a
Mb 13 1 78 95c
Fb 15 1 53 82c
Dog M & F 60 29 90d
Rabbit M 95 2 93c

a: includes dose found in 14CO2 and carcass; 120-h collection

b: bile-duct cannulated rats

c: includes dose found in gastrointestinal tract and carcass; 24-h collection

d: 48-h collection

e: 24-h collection

In rats, the differences between the excretion data for the two sexes were statistically significant. Extensive biliary excretion and enterohepatic recirculation was observed in both sexes. In the urine, propofol was completely metabolized prior to elimination. In the feces, propofol comprised ∼ 10% and 6% of the dose in male and female rats, respectively. The presence of propofol in the feces may be due to hydrolysis of propofol glucuronide. The radioactivity in theurine consisted of the 4-glucuronide and 4-sulphate conjugates of 2,6-diisopropyl 1,4 quinol and 4-sulphate of 2-(1-propionic acid)-6-isopropyl 1,4 quinol.

In dogs, the urine contained the 4-substituted glucuronic acid and sulphate conjugates of 2,6-diisopropyl 1,4-quinol and minor metabolites; unchanged propofol was < 1%. The feces contained 2,6-diisopropyl 1,4-quinol and some uncharacterized polar metabolites. At 2 minutes, the blood concentration of radioactivity was 10.02 µg equivalents/mL, that of propofol was 2.7 µg/mL, constituting 26% of total radioactivity. At 2 hours, propofol comprised only ∼ 1% of radioactivity.

In rabbits, urinary radioactivity consisted of the 4-glucuronide and 4-sulphate conjugates of propofol and 2,6-diisopropyl 1,4-quinol. Unchanged propofol was not detected. At 2 minutes, the blood concentration of radioactivity was ∼ 30 µg equivalents/mL, that of propofol was 15.9 µg/mL, constituting 53% of total radioactivity. At 2 hours, propofol represented ∼ 2% radioactivity.

Binding to Plasma Proteins

Propofol was 98% and 97% bound to plasma proteins in the dog and rat, respectively, over a concentration range of 0.1 - 20 µg/mL. In the rabbit, binding was concentration dependent; propofol binding decreased from 97% at 0.5 µg/mL to 95% at 50 µg/mL.

Toxicology

Acute Toxicity

Studies in Rats and Mice

Rats and mice of the Alderley Park Albino strain received graded intravenous or oral doses of propofol. At each dose level, six male and six female animals were used. The drug was available as an emulsion for the i.v. studies and as a solution in soya bean oil for the oral studies. At the doses used, all animals became anaesthetized. Several rats and mice, both in the i.v. and oral studies, regained consciousness and then became re-anaesthetized before fully recovering. The LD50 values and observations are summarized in Table 4 below.

Table 4: LD50 values and observations in Rats and Mice
Species Route of admin LD50% mg/kg (95% Confidence Limits) Observations
Rats i.v. 42 (38 - 46) Death occurred within 5 minutes of dosing.
oral 600 (540 - 660) The majority of rats died 1 to 3 days after propofol administration. Following recovery from anaesthesia, several rats exhibited decreased activity, piloerection, hunched posture and tremors.
Mice i.v. 53 (46 - 60) Death occurred within 2 minutes of dosing and was due to respiratory depression.
oral 1230 (1010 - 1500) The majority of mice died 1 to 2 days after propofol administration. During anaesthesia, both the rate and depth of respiration was decreased. Following recovery from anaesthesia, several mice exhibited locomotor incoordination and tremors.
Single-Dose Tolerance Study in Rabbits

Three male and three female Dutch rabbits received propofol, 15 mg/kg, by the intravenous route. The drug was given at a rate of 0.5 mg/kg/second. All rabbits became lightly anaesthetized, with 6/6 rabbits retaining their pedal reflex and 2/6 rabbits retaining their palpebral reflex. Ten to 15 minutes after dosing, all rabbits recovered completely without any untoward effect.

Long-Term Toxicology

One-Month Toxicity Study in Rats

Five groups of albino rats were dosed daily for 28 days. Injections were given intravenously into the tail vein. Group I received saline, Group II the emulsion vehicle, Groups III, IV and V propofol at doses of 5, 10 and 15 mg/kg/day, respectively.

Propofol induced anaesthesia in a dose-dependent manner; at 5 mg/kg rats were not anaesthetized while the duration of anaesthesia was significantly longer at the 15 mg/kg than at the 10 mg/kg dose. With repeated administration, the duration of anaesthesia became prolonged and on Day 26, anaesthesia lasted significantly longer than on Day 1.

High dose male rats gained slightly but significantly less weight than control rats (131 versus 150 g). In female rats, weight gain was slightly less in all treated animals, however, the effect was not dose-related. Urine volume was significantly but not dose-dependently elevated on Day 26 in all propofol-treated rats. In female rats, relative kidney weights were significantly and dose-dependently elevated in all propofol-treated groups.

One-Month Toxicity Study in Dogs

Five groups of Beagle dogs were dosed intravenously over a 30-day period. Group I received saline, Group II the emulsion vehicle, and Groups III and IV propofol at doses of 5 and 10 mg/kg/day, respectively. Group V received propofol, 30 mg/kg 3 times weekly for a total of 13 doses.

Each dose consisted of a 7.5 mg/kg bolus dose and an infusion of 0.5 mg/kg/min for a total of 22.5 mg/kg.

Each group was comprised of 5 male and 5 female dogs. In addition, 3 dogs/sex were used to evaluate recovery in the control and high dose groups.

Propofol induced anaesthesia in a dose-dependent manner. With repeated administration, the duration of anaesthesia became prolonged and on Day 28, anaesthesia lasted significantly longer than on Day 1.

During the 30-day treatment period, Hb, RBC and PCV values declined below the normal range in a few animals. On Day 30, abnormally low values were recorded in 3/10 dogs in both Groups III and IV. (In both groups, the same three dogs were affected.) In Groups II and V, 1/16 dogs each showed similar changes.

Reproduction and Teratology

Fertility and Reproductive Performance in Rats

Three groups of 50 rats each were dosed intravenously with the vehicle or propofol at doses of 10 or 15 mg/kg/day for two weeks prior to mating, during the mating period to untreated males and up to Day 7 of gestation. Generally, reproductive studies require that treatment be continuedduring both gestation and lactation, thus, this study provides information about propofol’s effect upon fertility but not necessarily upon reproduction.

Approximately half of the females of the F0 generation were sacrificed on Day 21 of pregnancy. The remainder were allowed to litter and rear their offspring to weaning at Day 22 of lactation. At weaning, two females and one male were selected from each litter to form the F1 generation. These animals were kept until sexually mature and then mated. As with the F0 generation, approximately half the females were sacrificed on Day 21 of pregnancy and the remainder were allowed to litter and rear their young to weaning, when the F1 dams and their pups (the F2 generation) were sacrificed.

The administration of propofol was associated with the following changes:

In the F0 generation, treated rats gained significantly less weight than controls prior to mating (9.7, - 0.8 and 1.7 g in the control, low and high dose groups, respectively). However, weight gains between Days 7 and 16, or 1 to 21 of pregnancy, were similar in all three groups.

Gestation period was dose-dependently decreased. In the control, low and high dose groups 9.5, 16 and 33% of the rats, respectively delivered on Day 21, rather than Day 22.

Survival of the F1 generation pups was lower in the treated groups. On Day 1, the number of alive pups was similar in all three groups. From Day 5 on, survival in treated groups was lower. Numerical values on Day 22 were as follows: 73, 49 and 52% of pups were alive in the control, low and high dose groups, respectively.

Pups which died, were subjected to necropsy. None showed soft tissue abnormalities, however, reduced vertebral ossification was present in 13, 38 and 40% of pups in the control, low and high dose groups, respectively.

Postimplantation loss (as a % of implants) in the F1 generation was higher in rats born to high dose animals (2.3, 1.2 and 15.6% in control, low and high dose rats, respectively).

Teratology Study in Rats

Four groups of 40 mated female rats each were dosed intravenously with the vehicle or propofol at doses of 5, 10 or 15 mg/kg/day from Day 6 to Day 15 of pregnancy. The rats were sacrificed on Day 20 of pregnancy and the pups checked for internal and skeletal anomalies.

Maternal weight gain during Days 6 to 15 was significantly less in propofol-treated rats than in controls. The incidence of abnormal cranial ossification was higher in fetuses born to high dose dams than in control fetuses (19.9% versus 11.0%).

In rats, sacrificed on Day 15 of pregnancy, 10 minutes after the last dose, propofol was detected in maternal blood, amniotic fluid and the developing embryo. Drug concentrations increased linearly with increasing doses.

The study indicated that propofol is not teratogenic in rats at the doses studied.

Teratology Study in Rabbits

Four groups of 22 mated female rabbits each were dosed intravenously with the vehicle or propofol at doses of 5, 10 or 15 mg/kg/day from Day 6 to Day 18 of pregnancy. The rabbits were sacrificed on Day 28 of pregnancy.

Maternal weight gain during Days 6 to 18 was less in propofol-treated rabbits than in controls. Incomplete sternebral ossification increased dose-dependently in fetuses born to propofol treated dams as compared to control fetuses.

Propofol was detected in maternal blood, amniotic fluid and embryonic tissue. Drug concentrations increased in a dose-dependent manner.

The study indicated that propofol is not teratogenic in rabbits at the doses studied.

Perinatal and Postnatal Study in Rats

Three groups of 22 rats each were dosed intravenously with the vehicle or propofol at doses of 10 to 15 mg/kg/day from Day 16 of gestation through Day 22 of lactation. The number of rats in whom treatment was completed was 18, 16 and 12, in the control, low and high dose groups, respectively. In the high dose group, four dams died during dosing, the cause of death might have been due to respiratory depression. In addition, mothers were sacrificed if the litters died. Maternal weight gain, during the last week of pregnancy, was significantly less in high dose rats than in control animals (47.1 versus 60.3 g). Litter survival on Day 22 was slightly but dose-dependently decreased; the percent of litters which survived was 65, 61 and 53% in the control, low and high dose groups, respectively.

Propofol did not affect the gestation period, maternal weight gain during lactation or the weight gain and developmental landmarks of the litter.