Source: Health Products and Food Branch (CA) Revision Year: 2021
Therapeutic classification: Topical acne therapy
The precise mechanism of action of tretinoin on the skin is not fully understood. It is known that tretinoin is both pharmacologically and structurally related to vitamin A which regulates epithelial cell growth and differentiation. Tretinoin itself is known to have an irritant and keratolytic effect on the skin. These two actions which occur simultaneously have been shown histologically in both animal and man to be associated with an increased growth rate and with a decrease in the cohesiveness of the epidermal cells. The result is a slightly thickened epidermis with an accelerated turnover rate and shedding of keratinized cells as very fine barely perceptible scales.
In acne vulgaris the induced fine scaling of the skin surface is accompanied by an increased production of less cohesive epidermal sebaceous cells, which consequently flow out of the follicle at a more rapid rate. The thickened mass of sebaceous cellular debris, the comedones appear to be initially extruded and then prevented from recurring by these actions. Histopathologically, acne is the impaction plus distension of the sebaceous follicles by tightly packed horny cells and disruption of the follicular epithelium. It has been postulated that tretinoin inhibits the synthesis or quality of the substance which binds the horny cells within the sebaceous follicle.
Tretinoin is a known metabolite of vitamin A. It appears to form oxidation products which are excreted in the urine and glucuronides excreted in the feces.
In human cutaneous absorption of retinoic acid was studied by application of 3 grams of 14C labelled 0.1% retinoic acid cream on 200 cm² of skin. After administration, radio-activity was detected in samples of blood, urine, stool and on skin occlusive dressings.
In subjects pre-treated with unlabelled material, slight increases in their blood radio-activity were observed 8 hours after application of the labelled material. In patients not pre-treated, no significant increases in radio-activity were observed.
Urine recovery studies in the subjects not pre-treated showed a 1.24 to 2.60% (mean: 1.82%) urinary excretion of the applied dose. The mean urinary excretion of the pre-treated subjects was 4.45%. Between 0.3 and 2.89% (mean: 1.58%) of the material was recovered in the stool of the pre-treated subjects. Extraction of radio-activity from skin occlusive dressings accounted for 73 to 96% (mean: 85.9%) of the applied dose.
In a further study, 2 and 4 hours after application of radio-actively labelled tretinoin to normal human skin, tretinoin was minimally detectable in the horny layer and sebaceous glands, but appreciably higher levels were found in the hair follicles and apocrine glands. After 24 hours, no penetration of radio-activity was detected beyond the Malpighian layer.
No systemic exposure of clinical significance is expected to arise if renal and hepatic impairment is present during topical use of tretinoin. This is because there is negligible percutaneous absorption of tretinoin when applied topically.
Clinical evaluation of the photosensitivity potential of topical STIEVA-A cream (0.3%, 0.1% and 0.05%) in one short-term study has shown the preparation to be free of phototoxic properties.
Relatively large systemic doses of tretinoin produced minor changes in the circulatory system of the cat. With 100 mg/kg, reduced perfusion in the hind extremities was noted, but there was no influence on blood pressure or respiration. Using 250 mg/kg, a mild reduction in blood pressure and a slight increase in pulse rate and circulation in the hind extremities were apparent. At a higher dose (1000 mg/kg) a pronounced increase in blood pressure and irregular respiration were observed; cardiac arrest followed fifteen minutes later.
Tretinoin, when administered orally or intraperitoneally, was shown to have a therapeutic effect on chemically induced skin papillomas and skin carcinomas in mice. The extent of the regression of the papillomas appeared to be dependent on the dose and duration of treatment. Tretinoin was also shown to have not only a prophylactic effect on the induction of papillomas but on the development of carcinomas in mice. It has been observed in mice, that tretinoin applied to experimentally produced dermatologic wounds, stimulated wound healing.
The effect of tretinoin on the survival of skin grafts in mice has been investigated. Tretinoin is thought to increase the susceptibility of skin homographs to the process of immunological rejection.
In several studies, tretinoin was administered orally to rats. It appears that little, if any, free tretinoin could be detected in the bile. Retinoyl β-glucuronide is apparently the only naturally occurring metabolite in rat bile. The glucuronide undergoes ester interchange or dehydration reactions which result in the formation of all trans- or cis-methyl retinoates and retinoyl β-glucurono-g-lactone, respectively. Retinoyl ß-glucuronide was also identified in the liver and intestine.
In the animals receiving the 0.05% solution decreased motor activity, hypnosis, salivation and vasodilation occurred. Tretinoin pure substance suspended in 5% gum acacia produced sedation, respiratory depression, diarrhea and alopecia in mice and rats. In neonatal rats receiving the pure substance, cyanosis and stunted growth were noted.
In a dog tolerance study, tretinoin pure substance was tolerated at an oral dose of 320 mg/kg. A single oral dose of 10 mL/kg of the cream formulation (0.3%) produced emesis and an elevation of AST (SGOT) and ALT (SGPT) levels.
In another dog tolerance study, 2 mL/kg of the solution formulation produced emesis and the polymorphonuclear leucocyte/lymphocyte ratio increased in one dog.
Tretinoin was administered orally to rats at levels of 0.78, 1.56, 3.12, 6.25 or 12.5 mg/kg/day for 11 days. All the high dose animals died within five days and one animal from each of the next three lower dose groups died during the study, while all animals survived at the lowest dose level. Intestinal irritation and diarrhea were noted. Skeletal fractures were observed in several animals.
In a four-week oral study in rats (2.5, 5, 10 or 20 mg/kg tretinoin per day), body weight gain was poor in the 20 mg/kg/day dose group. No bone fractures were observed in this study.
In a subsequent nine-week study in rats, tretinoin was administered orally at 1.56 and 3.12 mg/kg/day levels and no mortality occurred. Females had a slight increase in body weight gain and the males showed a slight decrease.
Four groups of rats received topical applications of a 0.3% cream at levels corresponding to 0, 1.5, 3 or 6 mg/kg/day of tretinoin 5 days per week for thirteen weeks. Food consumption and body weight gain were slightly reduced in the high dose group. Skin lesions with irritation and inflammation were noted and appeared to be dose dependent. Elevated total and polymorphonuclear leucocyte counts were observed in all dose groups. With the exception of a 3 mm mammary tumor in a control animal, there were no gross changes observed at autopsy. Microscopic examination of the skin revealed focal ulcerations and inflammatory changes of significant degree in the high and mid dose groups.
In another thirteen-week rat study, 6 mg/kg of tretinoin per day administered 7 days per week in the diet was well tolerated, although body weight gain, red blood cell count, packed cell volume, hemoglobin concentration and serum protein values all decreased.
On the other hand, plasma alkaline phosphatase values were markedly elevated. Histological examination revealed hyperplasia of blood-forming elements, increase in number and size of Kupffer liver cells, hydropic changes in the protoplasm of hepatocytes, increased number of foam cells and lymphatic elements of the lung, thinning of the epidermis and proliferation around the hair follicles.
In a thirteen-week dog study, tretinoin was administered orally to four groups of dogs at dose levels of 0, 3, 10 or 30 mg/kg/day 7 days per week. No mortality occurred in any of the groups. In the high dose group, one dog lost about 25% of his initial body weight. Eczema, acanthotic proliferation of the epidermis and diarrhea were also noted in the 10 and 30 mg/kg groups. Low erythrocyte count, hemoglobin concentration on and packed cell volume were noted in the 30 mg/kg group. Changes in the albumin and gamma globulin fractions were seen and blood sedimentation rates increased in the two highest dose groups. Lack of spermatogenesis and atrophy of the tubular epithelia occurred; there was hyperplasia of the blood-forming elements in bone marrow in the high dose group.
Eye and skin irritation studies were performed on rabbits with the tretinoin cream formulation at concentrations ranging from 0.01% to 0.5%. In the eye irritation test slight reddening of the conjunctiva occurred. Very slight edema and welldefined to moderate erythema were produced when applied to abraded and unabraded rabbit skin.
In subsequent irritation studies in rabbits, tretinoin, a 0.3% cream and a placebo cream were compared. The same degree of irritation was noted in the three groups. Tretinoin substance produced slight erythema, while the cream and placebo produced well-defined erythema and slight edema to rabbit skin.
In another study, the 0.05% tretinoin solution and a placebo were tested in rabbits. There appeared to be a very slight reddening of the conjunctiva and very slight discharge with both placebo and test solution groups. The placebo and test solution were considered non-irritating to the skin.
Female mice received tretinoin in oral doses of 1, 3, 9, 17, 43, 86 or 130 mg/kg from the 9th to 10th day of gestation. A slight increase in the incidence of skeletal malformations was observed in the low dose group (1 mg/kg). A pronounced teratogenic effect was produced with 3 mg/kg and higher doses. Multiple malformations of the head (cleft palate, exencephaly) were observed most frequently.
A slight increase in rate of resorption occurred at 3 mg/kg. With 9 mg/kg, 50% of all implanted embryos were resorbed. At still higher doses complete resorption occurred.
In a study in which 10 mg/kg/day was administered by gavage to 11 pregnant monkeys from Days 20 to 45 of gestation several teratogenic defects were observed. Specific defects such as cleft palate, auricular malformation, open eye with unilateral ablepharia, kyphosis, scoliosis, missing digits and severe curvature of the radius were observed6. Vaginal hemorrhage was observed frequently in the mothers. Abortion or fetal death with intrauterine retention (in 6 of the 11 mothers) was also observed. Three normal fetuses resulted, two of which aborted before term.
In one study, no teratogenic effects were seen in the fetuses when vitamin A acid was topically applied daily to the skin of pregnant rats during the second third of gestation.
Results from topical teratology studies in rats and rabbits have been inconclusive.
Carcinogenicity studies with STIEVA-A have not been conducted. Studies in hairless mice suggest that concurrent dermal exposure to isotretinoin, an isomer of tretinoin, may enhance the tumorigenic potential of ultraviolet irradiation.
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