Source: Health Products and Food Branch (CA) Revision Year: 2017
Flupentixol is a thioxanthene derivative with antipsychotic properties.
The exact mechanism of action of flupentixol has not been established. Its effects resemble those of the phenothiazine, fluphenazine, in that it belongs among the antipsychotic drugs which are less likely to cause sedation and hypotension, but have greater propensity for producing extrapyramidal reactions.
The kinetics is linear.
Flupentixol dihydrochloride is well absorbed from the gastrointestinal tract. Oral bioavailability is about 40%. Based upon radioisotope monitoring in man, the drug reaches maximum serum concentrations within 3 to 8 hours.
Steady state plasma levels are achieved in about 7 days. The mean minimum steady state level corresponding to 5 mg flupentixol orally once-a-day was about 1.7 ng/ml (3.9 nmol/l).
The highest levels of flupentixol as reflected by radioactivity count are found in the lungs, liver, and spleen, while concentrations in the brain are considerably lower, and only a little higher than concentrations found in the blood.
The apparent volume of distribution (Vd)β is about 14.1 l/kg. The plasma protein binding is about 99 %.
Flupentixol is metabolized by sulfoxidation, dealkylation (splitting of the distal ethanolic group in the side chain) and conjugation to glucuronic acid. The metabolites of flupentixol are devoid of psychopharmacological activity.
In the rat, flupentixol dihydrochloride is metabolized in the liver to the sulphoxide and glucuronide derivatives. In the feces, it is found mainly in the unchanged state and in the urine as the unchanged drug with the sulphoxide and glucuronide derivatives.
The more hydrophilic metabolites, sulfoxides and glucuronides are excreted with urine, the more lipophilic ones, flupentixol and dealkyl-flupentixol, with feces. Quantitatively, the fecal excretion dominates.
The elimination half-life (T½β) is about 35 hours and the mean systemic clearance (Cls) is about 0.29 l/min.
The kinetics is linear.
The esterification of flupentixol results in the slow release of the drug from the injection site with consequent prolongation of duration of action.
Studies in rats and dogs with 3H-flupentixol decanoate have revealed that flupentixol decanoate diffuses slowly from the oil solution into the extracellular fluid from where it is distributed via the blood stream to the different tissues of the body.
In pharmacokinetic studies measuring flupentixol blood levels, peak concentrations of the drug were found between days 4 and 7, following intramuscular injections of 40 mg of Fluanxol Depot 2% or 10%. It could still be detected in the blood three weeks after injection.
The highest levels of flupentixol as reflected by radioactivity count are found in the lungs, liver, and spleen, while concentrations in the brain are considerably lower, and only a little higher than concentrations found in the blood.
The apparent volume of distribution (Vd)β is about 14.1 l/kg. The plasma protein binding is about 99 %.
Flupentixol is metabolized by sulfoxidation, dealkylation (splitting of the distal ethanolic group in the side chain) and conjugation to glucuronic acid. The metabolites of flupentixol are devoid of psychopharmacological activity.
Flupentixol decanoate is efficiently hydrolized in vivo to flupentixol which is present in all tissues of the body.
With an estimated half-life of 3 weeks (reflecting the release from the depot) steady state conditions will be attained after about 3 months' repeated administration. The half-life of the drug calculated from excretion data has been shown to be eight days for the rat and about 12 days for the dog. Peak serum levels occur within the first 24 hours in rats and at 7 days after injection in dogs, but significant levels of radioactivity are found up to five weeks after administration.
Flupentixol reduces spontaneous activity in mice and induces a cataleptic state as determined by the vertical rod test. The drug antagonizes amphetamine-induced stereotyped behaviour and apomorphine-induced compulsive gnawing in rats as well as methylphenidate-induced compulsive gnawing in mice. It is also effective in preventing apomorphine-induced emesis in dogs.
Flupentixol inhibits the conditioned and, at higher doses, the unconditioned avoidance response in rats. It is also effective in releasing conflict-suppressed behaviour in rats. Flupentixol provides some protection against amphetamine-induced stimulation prolongs alcohol- and barbiturate-induced sleeping time in mice in only very high doses indicating a very weak sedative action in clinical use. It protects rats against isoniazid and pentetrazol convulsions, and, in higher doses, against electroconvulsions.
Flupentixol displays very weak anticholinergic activity in isolated guinea pig ileum and weak adrenolytic activity. It does not inhibit monoamine oxidase, nor does it inhibit the reuptake of adrenergic transmitters of adrenergic nerve endings.
Flupentixol antagonizes the effect of dopamine on cyclic AMP in the olfactory tubule and nucleus accumbens in the rat and antagonizes the dopamine agonist 2-amino-6,7-dihydroxyl-1,2,3,4,tetrahydro-napthalene in the striatum.
With the exception of minor drops in blood pressure seen when the drug is given by the intravenous route, it is without effect on the cardiovascular system of dogs. Blood pressure was also reduced by flupentixol in anesthetized rats and cats.
Like most other neuroleptics, flupentixol inhibits the prolactin inhibiting factor, resulting in an increase in serum prolactin levels.
| Route of Administration | LD50 in mg/kg | |
|---|---|---|
| Mice | Rats | |
| I.V. | 71 ± 9 | 74 ± 10 |
| I.P. | 240 ± 47 | 213 ± 28 |
| I.M. | >400 | > 400 |
| P.O. | 875 ± 48 | 1530 ± 257 |
One male dog administered a single dose of 20 mg/kg intramuscularly became sedated after 15 minutes. Sedation progressed, and one hour post-injection the dog was completely relaxed without any muscle tone and could not be aroused. 18 to 24 hours later the dog was still heavily sedated and could not stand up, although the eyes were open. Normal behaviour was observed 48 hours post-injection.
Parenteral administration of flupentixol dihydrochloride produced extensive local tissue reaction in all species.
The parenteral LD50 of flupentixol decanoate is greater than 200 mg/kg in rats. Mice administered 400 mg/kg orally or parenterally survived for three days. The majority died between the fourth and tenth day after becoming sedated and being unable to eat or drink.
1 mg/kg given to rats subcutaneously for 30 consecutive days produced, apart from local reactions, some sedation with concomitant minor depression of food intake and growth and a decrease in uterine weights.
In a 3-month study, rats received 15 to 60 mg/kg/day of flupentixol dihydrochloride in the diet and, in another study, 10 to 40 mg/kg/day was consumed in the diet for a period of one year. Sedation, reduced growth and decreased uterine weights were observed at all dose levels.
Two 6-month studies were conducted in dogs with doses of flupentixol dihydrochloride ranging from 0.5 to 20 mg/kg/day. The drug was given orally in tablet form. At 0.5 mg/kg, the only effects noted were a slight increase in serum sodium values after 7 weeks of drug administration, a slight decrease in serum sodium after 19 and 25 weeks, and lower serum gamma globulin than in controls after 19 weeks (only one dog of each sex received the drug for 6 months).
At the 2 mg/kg dose, some of the dogs showed an increase in serum alpha globulin and transaminase levels. At post mortem, a decrease in absolute and relative uterine and prostate weights was observed, and the histopathology showed increased incidence of pigment in liver cells.
20 mg/kg produced progressive sedation, lethargy, ataxia and relaxed nictitating membrane during the first hour after dosing, followed by sleep, catatonia and shivering for the next 4 to 6 hours. These effects wore off by the following morning, but reappeared after each dosing throughout the experimental period. Body weight gain was depressed and all animals in the group showed increased alpha globulin levels after 3 or 6 months of drug administration. Some of the dogs had also increased alkaline phosphatase levels. Post mortem examination showed a substantial decrease in absolute and relative uterine and prostate weights, and histopathological examination showed pigment in the liver cells of all animals in this group as well as periarteritis nodosa in 3 of 6 dogs.
10 or 15 mg/kg of flupentixol decanoate was administered twice weekly to rats for seven weeks. It was associated with some inhibition of growth secondary to sedation causing reduced food intake, a decrease in red blood cells (males only), and an increase in serum creatinine. At post mortem, the only significant finding, apart from a slight decrease in liver weight in males, was a localized subcutaneous reaction around the oil droplets. During a ten-week recovery period the oil droplets disappeared gradually, but not completely.
Dogs were administered 0, 2 and 6 mg/kg/week intramuscularly for 26 weeks. The only significant findings were a heavy local reaction with some encapsulated small oil drops at the injection site, slight swelling of the popliteal gland (16th week), some inter- and intramuscular fibrosis with hyperplasia of the popliteal lymph node and an apparently dose-related transient increase in alpha globulins with concurrent decrease in beta and gamma globulins.
5, 10, 15 and 25 mg/kg/day of flupentixol dihydrochloride was administered orally to mice on days 6 to 12 of gestation. The results are suggestive of an abortifacient effect at all dose levels, as only 60% and 47% respectively of the dams at the two lowest dose levels and none at the higher dose levels went to term. There were no obvious signs of fetotoxicity in the young born in the lower dose groups.
In the rat, three studies were carried out, using Wistar and Sprague-Dawley strains. In one experiment, 50 to 100 mg/kg/day was administered by gavage on day 4 to 13 of gestation; in a second experiment, 5 to 50 mg/kg/day was given by gavage on days 2 to 21; and in a third study, 15 and 30 mg/kg/day were given in the diet from 3 weeks prior to mating until weaning.
At 100 mg/kg, the dams displayed hypersensitivity and retarded growth with 2 dams dying before parturition. The resorption rate was 45%. Resorptions also occurred at 50 mg/kg in the first study. In the second study, 2 dams in the 50 mg/kg group died, the incidence of resorptions was increased, and the dams that bore viable young were poor mothers, resulting in most of the pups dying before weaning. Three pups in the 50 mg/kg group and one in the 25 mg/kg group had cleft palates. With 5 mg/kg, there was a 50% reduction of litter size at weaning. In the third study, in which the drug was administered before mating and continued until weaning, there were no births in the 30 mg/kg group and only one dam had a single resumption site, indicating that excess sedation interfered with mating. In the 15 mg/kg group only 4 of 20 dams bore viable young; these had no abnormalities.
New Zealand white rabbits were given 2, 20 and 40 mg/kg flupentixol dihydrochloride per day on days 6 to 16 of gestation. Abortifacient effects were noted at all dose levels and the dams in the mid and high dose groups were hypersensitive. Reduced implantation rates occurred with 40 mg/kg.
Flupentixol decanoate was administered on day 6 of gestation to mice and rats (10 and 20 mg/kg s.c.) and to rabbits (2 and 6 mg/kg i.m.). Dams were not adversely affected. However, an abortificacient effect occurred in mice receiving 20 mg/kg.
In reproductive studies with flupentixol hydrochloride, a similar abortifacient effect was noted in mice and rabbits. In rats, fetotoxic effects (reduced conception rates, increased resorptions, retarded growth and poor weaning performances) were observed. Four cases of cleft palate were found in three litters of rats receiving 50 or 25 mg/kg/day.
A 104 week carcinogenicity study was performed in rats. 250 male and 250 female rats of the Wistar strain were allocated to 5 groups of 50 males and 50 females. The animals received flupentixol dihydrochloride at dosages of 1.0, 3.5 or 12.0 mg/kg/day orally, mixed in the diet. Two control groups received untreated diet. At the end of the 104 week treatment period, all surviving rats were killed and subjected to a full necropsy with tissue retention. Aside from red or brown staining in all groups including controls, with a slight increase in the frequency and severity in animals of both sexes receiving the drug at 12.0 mg/kg/day, no signs of reaction to treatment were observed.
Marked reductions in body weight gain were seen in both sexes receiving 12.0 mg/kg/day. The weights achieved by the males and females at this dose after 104 weeks were 70% of respective control values.
Males receiving 3.5 mg/kg/day showed an inferior growth pattern to controls from early in the study, with achieved weights at termination being 87% of controls. The females at this dose level remained similar to controls throughout the treatment period. Males receiving 1.0 mg/kg/day showed a significant reduction in body weight gain during part of the study, when compared to the control groups. This was not present during weeks 100 and 104. Females at this dose level remained similar to controls throughout the treatment period.
The overall food consumption values showed marked reductions throughout the treatment period in both sexes at 12.0 mg/kg/day; with males achieving 86% and females 83% of control values. A reduction was also evident in both sexes in the group receiving 3.5 mg/kg/day, with overall food consumption values of 94% of control values, respectively.
Treatment was associated with an increase in the accumulation of hemosiderin in the liver of females receiving 12.0 mg/kg/day.
Males receiving 12.0 mg/kg/day showed a statistically significant increase (p>0.01) in the incidence of pituitary adenomas. The nature and biological characteristics of other tumours diagnosed were consistent with those occurring commonly in the rat and were considered to be of no significance.
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