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Serentil Pharmacology, Pharmacokinetics, Studies, Metabolism - Mesoridazine Besylate
Serentil Pharmacology, Pharmacokinetics, Studies, Metabolism - Mesoridazine Besylate
CLINICAL PHARMACOLOGY
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Based upon animal studies, Serentil® (mesoridazine besylate),
as with other phenothiazines, acts indirectly on reticular formation,
whereby neuronal activity into reticular formation is reduced without
affecting its intrinsic ability to activate the cerebral cortex. In addition,
the phenothiazines exhibit at least part of their activities through depression
of hypothalamic centers. Neurochemically, the phenothiazines are thought
to exert their effects by a central adrenergic blocking action.
Pharmacological studies in laboratory animals have established that
Serentil® (mesoridazine besylate) has a spectrum of pharmacodynamic
actions typical of a major tranquilizer. In common with other tranquilizers
it inhibits spontaneous motor activity in mice, prolongs thiopental and
hexobarbital sleeping time in mice and produces spindles and block of
arousal reaction in the EEG of rabbits. It is effective in blocking spinal
reflexes in the cut and antagonizes d-amphetamine excitation and toxicity
in grouped mice. It shows a moderate adrenergic blocking activity in vitro
and in vivo and antagonizes 5-hydroxytryptamine in vivo. Intravenously
administered, it lowers the blood pressure of anesthetized dogs. It has
a weak antiacetylcholine effect in vitro.
The most outstanding activity of Serentil® (mesoridazine besylate)
is seen in tests developed to investigate antiemotive activity of drugs.
Such tests are those in which the rat reacts to acute or chronic stress
by increased defecation (emotogenic defecation) or tests in which “emotional
mydriasis” is elicited in the mouse by an electric shock. In both of these
tests Serentil® (mesoridazine besylate) is effective in reducing
emotive reactions. Its ED50 in inhibiting emotogenic defecation in the
rat is 0.053 mg/kg (subcutaneous administration). Serentil®
(mesoridazine besylate) has a potent antiemetic action. The intravenous
ED50 against apomorphine-induced emesis in the dog is 0.64 mg/kg. Serentil®
(mesoridazine besylate), in common with other phenothiazines, demonstrates
antiarrhythmic activity in anesthetized dogs.
Metabolic studies in the dog and rabbit with tritium labeled mesoridazine
demonstrate that the compound is well absorbed from the gastrointestinal
tract. The biological half life of Serentil® (mesoridazine
besylate) in these studies appears to be somewhere between 24 to 48 hours.
Although significant urinary excretion was observed following the administration
of Serentil® (mesoridazine besylute), these studies also suggest
that biliary excretion is an important excretion route for mesoridazine
and/or its metabolites.
Toxicity Studies
Acute LD50 (mg/kg):
| Route |
Mouse |
Rat |
Rabbit |
Dog |
| Oral |
560±62.5 |
644±48 |
MLD= 800 |
MLD= 800 |
| I.M. |
— |
509M 584F |
405 |
— |
| I.V. |
26±0.08 |
— |
— |
— |
Chronic toxicity studies were conducted in rats and dogs. Rats were administered
Serentil® (mesoridazine besylate) orally seven days per week
for a period of seventeen months in doses up to 160 mg/kg per day. Dogs
were administered Serentil® (mesoridazine besylate) orally
seven days per week for a period of thirteen months. The daily dosage
of the drug was increased during the period of this test such that the
“top-dose” group received a daily dose of 120 mg/kg of mesoridazine for
the last month of the study.
Untoward effects which occurred upon chronic administration of high dose-levels
included:
Rats: Reduction of food intake, slowed weight gain, morphological
changes in pituitary-supported endocrine organs, and melanin-like pigment
deposition in renal tissues.
Dogs: Emesis, muscle tremors, decreased food intake and death
associated with aspiration of oral-gastric contents into the respiratory
system.
Increased intrauterine resorptions were seen with Serentil®
(mesoridazine besylate) in rats at 70 mg/kg and in rabbits at 125 mg/kg
but not at 60 and 100 mg/kg, respectively. No drug related teratology
was suggested by these reproductive studies.
Local irritation from the intramuscular injection of Serentil®
(mesoridazine besylate) was of the same order of magnitude as with other
phenothiazines.
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