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Purpose: To develop a simple pharmacodynamic (PD) assay for the evaluation of the bioequivalence of topically applied retinoid products., Methods: Daily applications of products containing tretinoin or adapalene were made to the forearms of human subjects for up to 21 days. Percutaneous absorption was enhanced through the use of polyethylene film occlusion (5 h). Pharmacologic activity was assessed through the daily measurement of three cutaneous responses intimately linked to retinoid-induced changes in epidermal differentiation: (1) erythema; (2) exfoliation (scaling/peeling), and (3) increased transepidermal water loss., Results: The PD model exhibited the sensitivity and specificity required to function as a bioequivalence surrogate. It was possible to differentiate between: (1) three concentrations of tretinoin in a commercial cream product line; (2) two concentrations of tretinoin in a commercial gel product line; (3) different vehicles (gel vs. cream) containing the same concentration of tretinoin, and (4) tretinoin and adapalene at the same concentration. The applicability of this model for bioequivalence testing was established by showing that it had sufficient power to determine that three test tretinoin cream products and two approved generic tretinoin gel products were equivalent to their corresponding reference products., Conclusions: A surrogate PD model to assess retinoid bioequivalence has been developed., (Copyright © 2012 S. Karger AG, Basel.)

Background: High intakes of vitamin A cause congenital malformations in experimental animals with elevated generation of retinoic acids (RA). Results in humans are conflicting., Objective: To evaluate plasma concentration-time curves of retinyl esters, retinol and their metabolites at increasing doses of vitamin A., Methods: An open-label dose-response study. Non-pregnant females (3 groups with n = 12; 18-40 years) received once daily oral doses of vitamin A palmitate up to 30,000 IU/day over 21 days. The area under the plasma concentration-time curve (AUC(24h)) served as indicator for exposure., Results: AUC(24h) of retinyl esters increased linearly with dose. Retinol concentrations were unaffected. All-trans RA exhibited a diurnal-like concentration-time profile (Cmax at 3 h; Cmin at 8 h), concentrations decreasing below pre-dose levels at 5 h and regaining pre-dose levels at 16 h. The maximum temporary increase in exposure was 33% (single dose) and 19% (repeated doses) above baseline, but AUC(24h) remained unaltered. AUC(24h) increased linearly with dose for 13-cis RA and 13-cis-4-oxo RA. Repeated doses caused a 25% increase in exposure with the highest vitamin A intake. Accumulation of 13-cis-4-oxo RA at 30,000 IU/day doubled compared to the 4,000 IU/day intake., Conclusion: Repeated oral doses of up to 30,000 IU of vitamin A in addition to dietary vitamin A were without safety concern. Safe doses are probably higher, since plasma concentrations and exposure to RA remained at levels earlier shown to be without increased risk of teratogenicity in pregnant women., (2005 S. Karger AG, Basel)

The efficacy of all-trans-retinoic acid (tRA) and all-trans-retinoyl beta-glucuronide (RAG), a water-soluble metabolite of vitamin A, in the topical treatment of acne is comparable. However, whereas 3.3 mM tRA shows side effects, 3.3 mM RAG does not. To assess the relative toxic and histologic effects (dermal and epidermal changes) of long-term (24-week) daily applications of tRA and RAG on the skin, separate skin patches were measured and marked dorsally on the skin of six 21-day-old, castrated male pigs. Each skin patch area was treated daily with a cream formulation containing either 3.3 mM RAG, 16.5 mM RAG, 33 mM RAG, 3.3 mM tRA, 16.5 mM tRA or blank cream. To serve as controls, one patch received no treatment, one patch received blank cream only and for 5.3 weeks one 'washed' patch was given daily application of 33 mM RAG with routine cleansing using a mild soap typical of skin care. The amount of cream used per square centimeter remained the same during the course of the study. Biopsy tissue was collected at -1, 0, 2, 4, 8, 12 and 24 weeks from 7 test patches. The 'washed' patch was biopsied once at the 5.3-week mark. Topically applied RAG cream (3.3 mM) resulted in significantly lower histologic scores when compared with scores from tissue treated with an equimolar concentration of tRA. The highest concentration of RAG tested (33.3 mM) resulted in a response comparable to that observed in the lowest tRA (3.3 mM) treated patch area. Daily cleansing of the test area receiving 33.3 mM RAG completely eliminated any clinical signs or negative histologic changes. In conclusion, long-term topical tRA treatment in young pigs, as in humans, showed dose-dependent adverse effects on the skin, whereas RAG treatment had significantly lower histologic changes and less irritation and/or inflammation., (Copyright 2002 S. Karger AG, Basel)

The biotransformation and tissue distribution of 9-cis-retinoic acid was investigated in hairless rats. Indeed, only limited information is available about the pharmacokinetics of 9-cis-retinoic acid. Assuming that the target site for retinoids is the skin, tissue distribution study is therefore particularly justified. Following single oral administration of 30 mg/kg of 9-cis-retinoic acid, the parent drug and five metabolites were detected in plasma. Additionally, concentrations of 9-cis-retinoic acid and metabolites were determined in the skin and seven other tissues. The distribution of 9-cis-retinoic acid was rapid in all of the organs studied (T(max)

Background: Retinoic acid, a metabolite of retinol, is formed in the skin of various species., Purpose: Formation rates have not been determined in a dynamic skin perfusion model which may show the dehydrogenation of retinol to be rate limited., Methods: (all-trans-) Retinol acetate, retinol, or retinoic acid was applied dermally with isopropyl myristate. The ears were single-pass perfused with 6% hetastarch or 5% bovine serum albumin in the buffer solution. The effluent was analyzed by HPLC for these substances., Result: No ester hydrolysis of retinol acetate was observed, nor did this substrate appear in the effluent. Retinol or retinoic acid were detected in the effluent. The absorption rate was linearly related to the dermally applied concentration density. The absorption rate of retinoic acid was 70 times larger than that for retinol. The formation rate of retinoic acid from retinol was rate limited (apparent Vmax: 0.08 pmol/min/cm2 skin)., Conclusion: Since retinoic acid is a recognized pharmacologically active ingredient in the skin, the dehydrogenation of retinol or retinal was also observed in the effluent of this skin perfusion model. The percutaneous retinol adds to the endogenous pool of retinoic acid by cytosolic dehydrogenation or microsomal oxidation elsewhere. The steady-state absorption rate of 0.1% retinoic acid in isopropyl myristate, referred to 500 cm2 of the human skin, would contribute about 20% of the daily requirement of vitamin A, without increase in endogenous retinoic acid plasma concentration.

The purpose of these studies was to compare directly the percutaneous absorption,excretion and metabolism of all-trans-retinoyl beta-glucuronide (RAG), a nontoxic retinoid, with all-trans-retinoic acid (RA) in the rat. Previously, it was demonstrated that topical treatment of human acne with either RAG or RA in cream resulted in a significant reduction of lesions. Whereas 0.1% RA showed adverse effects, concentrations of RAG up to 2.4% did not cause any adverse reactions. In the present studies, radiolabeled RAG or RA, dispersed in a water-based cream, was applied to the shaved dorsal skin of vitamin A-sufficient rats. Both RAG and RA were absorbed from the skin in a similar way. In both cases, radioactivity peaked in the plasma within 2-4 h and within the liver at 4-12 h. During a 7-day period, the overall excretion of radioactivity derived from RA and RAG in the feces and urine were similar, e.g. 17 and 12%, respectively. it is concluded that: (1) the transport, metabolism and excretion of topically applied radioactive RA and RAG are similar, although not identical, in the rat and (2) the toxic skin manifestations induced by RA but not by RAG cannot be attributed to major differences in their overall absorption, metabolism and excretion.

The aim of the study was to investigate the concentrations of Ro 10-1670 (acitretin) and its isomeric metabolite Ro 13-7652 (cis-acitretin) after multiple oral dosing of acitretin. We used a highly sensitive HPLC method for simultaneous determination of the 2 retinoids with a quantification limit of 2 ng/ml in plasma and 10 ng/g in total skin (epidermis and dermis). In hairless rats receiving orally 8 mg/kg acitretin once daily during 8 days, blood and skin samples were taken at different time points between 5 and 96 h after the last dose. After 96 h, appreciable concentrations of Ro 10-1670, but not Ro 13-7652 could be measured in the skin, whereas both isomers were below the quantification limit in plasma. In psoriatic patients treated with a once daily dose of 30 mg acitretin, blood samples and biopsies were taken after 1 month of treatment (i.e. under steady state conditions). 24 h after the last drug intake, skin concentrations of acitretin were approximately 10 times higher than those observed in plasma. Ro 10-1670 concentrations in the skin were approximately 3-5 times higher than for Ro 13-7652 and concentrations of both isomers were higher in lesional compared to uninvolved skin.

The major plasma metabolite of acitretin (trans-acitretin) is its 13-cis isomer, cis-acitretin. Interconversion of cis-acitretin to trans-acitretin was demonstrated in man following administration of a single oral dose of cis-acitretin. Plasma concentrations of Ro 13-7652 (cis-acitretin) and Ro 10-1670 (trans-acitretin) were much higher after cis-acitretin administration than after trans-acitretin administration. Surprisingly, these high concentrations were not associated with a clear therapeutic effect in dermatoses (e.g. psoriasis) which are usually responsive to oral retinoids. Interactions between the cis and trans isomers formed in vivo may explain the difference in therapeutic activity of each stereoisomer when administered orally.

In order to study the elimination of Ro 10-1670 (acitretin) and Ro 13-7652, its 13-cis-isomeric metabolite after chronic administration, determination of the residual plasma concentrations of these two compounds were assayed in 9 patients in a range of 22-30 days following cessation of a 2- to 7.5-month course with daily oral doses of 10-50 mg of acitretin. A highly sensitive HPLC method was used (2 ng/ml). Residual plasma concentrations of Ro 10-1670 were below the quantification limit in all cases. Residual plasma concentrations of Ro 13-7652 were below the quantification limit in 7 cases and respectively of 3 and 4 ng/ml in the other 2 cases. These data appear to confirm the absence of storage of acitretin even after an extended course of therapy.

The bioavailability, plasma transport and tissue distribution of various retinoids are largely determined by their physicochemical properties; some are extremely lipidsoluble whereas others are relatively hydrophilic. Isotretinoin, a 1st generation retinoid, lacks the problematic affinity for fat. Etretinate, a 2nd generation aromatic retinoid, has been shown to accumulate in both fat tissues and in the adrenals. Etretin, the main free-acid metabolite of etretinate, is less lipophilic and is presently being tested as an alternative drug. Arotinoid ethyl ester, a 3rd generation aromatic retinoid which has as yet only undergone limited trials, is extremely potent making pharmacological evaluation difficult. The search for more potent retinoids has not so far resulted in a complete resolution of the efficacy and toxicity of the drugs.

A 59-year-old woman with a history of papillary carcinoma of the thyroid gland developed three reddish nodules on the scalp. A skin biopsy showed a dermal tumor composed of sheets of clearly differentiated thyroid vesicles. Cutaneous metastases of thyroid carcinoma are very rare and this case is the first case confirmed by immunoperoxidase studies using monoclonal antithyroglobulin antibody. Positive reactions were obtained in colloid and at apices of thyrocytes. Monoclonal antibodies to human thyroglobulin may offer a unique opportunity to confirm the tissue origin of cutaneous metastasis.

Following oral administration of acitretin with food, peak plasma concentrations of unchanged drug (Ro 10-1670) are reached within 4 h. The mean absolute bioavailability of acitretin is 59% with high interpatient variability consistent with that of etretinate. Taking acitretin with food results in an increased and more consistent bioavailability. The drug appears to be extensively distributed throughout the body without unexpected accumulation and the elimination half-life is approximately 50 h. Acitretin has a profound pharmacokinetic advantage over etretinate because it is eliminated more rapidly from the body; etretinate is sequestered into fatty tissue due to its greater lipophilicity creating a deep compartment from which it is only slowly released. Acitretin is eliminated entirely by the metabolism and the resultant metabolites are excreted via the kidney and bile.

Chronic renal failure (CRF) interferes with the catabolism of retinol and is frequently associated with hypervitaminosis A. The effect of CRF on the plasma levels of etretinate (Tigason, Tegison), an aromatic retinoid, was therefore studied in 4 patients who were given the drug as part of a maintenance antipsoriatic regimen. The concentrations of the parent compound and its main metabolites (etretin and isoetretin) were monitored for 24 h after receiving a routine dose of the drug. In comparison with 4 non-CRF patients receiving similar maintenance doses of etretinate, although the CRF patients had higher peak levels of the parent compound (p less than 0.01), the levels of the metabolites were similar or lower. The plasma half-lives for all compounds were approximately the same in each group, indicating that the catabolism of the drug was not affected by CRF. However, elevated etretinate concentrations may increase the drug accumulation in fat tissues and thereby prolong the time required for final elimination of the drug.

A possible influence of the aromatic retinoid acitretin on the hypothrombinemic action of phenprocoumon was investigated in 10 healthy male volunteers, 22-33 years of age. In a run-in period of 17 days the prothrombin complex activity (Quick) of the subjects was adjusted by individual doses of phenprocoumon (range 1.5-3 mg/day) to a therapeutic level of around 20% (INR = 3.6). Afterwards the dosage regimens were kept unchanged until day 40 when 60 mg oral vitamin K1 were administered. From day 18 to day 28 once daily doses of 50 mg acitretin were applied concurrently with phenprocoumon. The mean (+/- SD) prothrombin complex activity increased slightly and steadily from 19 +/- 1% on day 10 over 22 +/- 1% on day 18 to 24 +/- 4% on day 28 and reached 27 +/- 4% on day 38 (the corresponding INRs were 3.30, 2.91, 2.71 and 2.46 respectively). There were, however, no relevant changes of the Quick values in any subject which could be attributed to acitretin. It can be concluded that, under the present experimental conditions, acitretin did not affect significantly the anticoagulant action of phenprocoumon.