Tazarotene cream for the treatment of facial photodamage: a multicenter, investigator-masked, randomized, vehicle-controlled, parallel comparison of 0.01%, 0.025%, 0.05%, and 0.1% tazarotene creams with 0.05% tretinoin emollient cream applied once daily for 24 weeks.

OBJECTIVE: To assess the safety and efficacy of 4 concentrations of tazarotene cream in the treatment of facial photodamage. DESIGN: Prospective weekly multicenter, investigator-masked, randomized, parallel-group study. SETTING: University hospitals and clinical research centers. PATIENTS: Three hundred forty-nine subjects with facial photodamage. INTERVENTION: Daily topical application of tazarotene cream (0.01%, 0.025%, 0.05%, and 0.1%) compared with its vehicle and with 0.05% tretinoin emollient cream. RESULTS: Tazarotene cream and tretinoin cream significantly improved mottled hyperpigmentation and fine wrinkles. At week 24, treatment success rates based on global responses were 67% (39 of 58 subjects) with 0.1% tazarotene, 52% (30 of 58 subjects) with 0.05% tazarotene, 36% (21 of 58 subjects) with 0.025% tazarotene, 41% (24 of 59 subjects) with 0.01% tazarotene, 55% (32 of 58 subjects) with 0.05% tretinoin, and 22% (13 of 58 subjects) with vehicle. Local adverse events, although more frequent with tazarotene at higher concentrations, were generally mild to moderate. CONCLUSIONS: Tazarotene in a cream formulation is safe and is associated with positive changes in the treatment of photodamaged facial skin.

Clinical pharmacokinetics and drug metabolism of tazarotene: a novel topical treatment for acne and psoriasis.

Tazarotene (AGN 190168) is a new acetylenic retinoid which is effective for the topical treatment of patients with stable plaque psoriasis and mild to moderate acne vulgaris. Topical gel application provides direct delivery of tazarotene into the skin. At 10 hours after a topical application of 0.1% tazarotene gel to the skin of healthy individuals and patients with psoriasis, approximately 4 to 6% of the dose resided in the stratum corneum and 2% of the dose distributed to the viable epidermis and dermis. Tazarotene is rapidly hydrolysed by esterases to its active metabolite, tazarotenic acid. Tazarotenic acid does not accumulate in adipose tissue, but undergoes further metabolism to its sulfoxide and to other polar metabolites and is rapidly eliminated via both urinary and faecal pathways with a terminal half-life of about 18 hours. Percutaneous absorption is similar between healthy individuals and patients with facial acne, leading to plasma concentrations below 1 microg/L. The systemic bioavailability of tazarotene (measured as tazarotenic acid) is low, approximately 1% after single and multiple topical applications to healthy skin. In patients with psoriasis under typical conditions of use, systemic bioavailability increased during the initial 2 weeks of treatment from 1% (single dose) to 5% or less (steady state). The increased bioavailability is probably related to decreases in plaque elevation and scaling due to successful treatment, resulting in a less effective skin penetration barrier to tazarotene. Steady-state concentrations of tazarotenic acid are achieved within 2 weeks of topical treatment in both healthy and psoriatic skin types. The large variability in plasma concentrations observed in patients with psoriasis is probably because of the large differences in lesional skin condition, the amount of drug applied and the surface area of application. There was no significant drug accumulation in the body with long term treatment of patients with psoriasis. Topical administration of tazarotene requires dosages much smaller than those usually required for oral retinoids, such as isotretinoin, acitretin and etretinate, and it delivers the drug directly into the target skin tissues. The low systemic absorption and rapid systemic elimination of tazarotene and tazarotenic acid results in limited systemic exposure. Thus, topical tazarotene has a low potential for systemic adverse effects and is effective in the treatment of patients with acne and psoriasis.

Hepatic cytochrome P-450 and in vitro drug metabolism in an overfed rat model of obesity.

Liver microsomes from obese and control Sprague-Dawley rats were compared for cytochrome P-450 content and the ability to metabolize various prototype substrates. Over a 40-week period, the obesity-producing energy-dense diet increased average total body mass by 50%, liver mass by 32%, and body fat mass by 292%. Spectrally detectable cytochrome P-450 per mg protein increased by 36% in hepatic microsomes from obese rats. The livers from obese rats also contained more cytochrome P-450 (87%), while microsomal protein, NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase, and UDP-glucuronosyl transferase per organ rose slightly (12-40%) but not significantly. No change in the specific activities of these enzymes occurred. Young and adult rats were transferred from pellet diet to energy-dense diet for 3 weeks to examine the influence of diet vs. obesity. This short-term dietary change increased microsomal protein per g liver as well as cytochrome P-450 per liver, per g liver, and per mg protein. Adult animals increased in body weight by 24%, making them overweight and borderline obese. However, young animals showed no increase in body or liver weight, suggesting a direct effect of the energy-dense diet on liver P-450. Dietary obesity thus increased both the relative and total amounts of liver cytochrome P-450 in rats, but not the specific activities of other enzymes. These changes in cytochrome P-450 are consistent with the increased clearance seen for several oxidized drugs in obese humans and suggest that the obese overfed rat represents a useful animal model.

The opposing effects of N-hydroxyamphetamine and N-hydroxyphentermine on the H2O2 generated by hepatic cytochrome P-450.

The effects of N-hydroxyphentermine (NOHP) and N-hydroxyamphetamine (NOHA) on hydrogen peroxide generated by rat liver microsomes and reconstituted preparations in the presence of NADPH were compared. In microsome incubations, NOHP caused an increase in H2O2 levels and NOHA caused a substantial decrease. When the substances were compared for cytochrome P-450-dependent H2O2 generation in reconstituted preparations, NOHA at mM blocked generation and NOHP had no effect. NOHP appears to be an uncoupler of the cytochrome P-450 system in microsomes whereas NOHA is a potent inhibitor, presumably because of its ability to form a metabolic intermediate complex. During the course of their effects on O2 reduction, NOHP and NOHA are themselves undergoing oxidation, NOHP to 2-methyl-2-nitro-1-phenylpropane and NOHA to phenylacetone oxime. The enzymatic natures of these oxidations differ. Thus, two closely related arylalkylhydroxylamines differ substantially in their interaction with cytochrome P-450 systems.

Conversion of N-hydroxyamphetamine to phenylacetone oxime by rat liver microsomes.

These in vitro studies indicate that N-oxidation of N-hydroxyamphetamine (NOHA) by rat liver homogenates yields phenylacetone oxime (PAOx) as the major metabolite. This oxidation was NADPH and oxygen dependent but was not appreciably increased in microsomes from phenobarbital-pretreated animals. The addition to microsomal incubations of superoxide dismutase (SOD), catalase (CAT), azide or mannitol did not alter the rate of oxidation, suggesting that O2-, H2O2, or OH' are not involved in this process. The reaction was minimally inhibited by a 2:1 ratio of CO/O2, and there was no significant reduction in the formation of product by the presence of diethylaminoethyl diphenylvalerate (SKF-525A) or 2,4-dichloro-6-phenylphenoxyethylamine (DPEA) in micromolar concentrations. Thus, although this NADPH-dependent N-oxidation pathway was catalyzed by rat hepatic microsomes, the data suggest that is was not a cytochrome P-450 mediated monooxygenase reaction.