The negligible systemic availability of retinoids with multiple and excessive topical application of isotretinoin 0.05% gel (Isotrex) in patients with acne vulgaris

Topical retinoids are therapeutically active at low pharmaceutical concentrations, i.e. in essence lack of penetration is not a problem. Thus studies on the cutaneous pharmacokinetics focus on the distribution pattern in the skin, the penetration pathways, the cutaneous metabolism, the systemic body load and the mode of excretion. Two basically different pathways have to be taken into account: the transepidermal pathway, which gives rise to a typical epidermal/dermal concentration gradient and which is certainly part of the mode of action in disorders of keratinization, and the transfollicular pathway, which sheds some light on the activity in follicular disorders like acne. The cutaneous part of the pharmacokinetics of retinoids depends largely on their chemical structure and thus differs. However, common features are relatively high cutaneous concentrations, whereas the spillover to the systemic compartment appears to be slow and small, giving rise to low or hardly detectable bodyloads. Concerning pharmacokinetics topical application of retinoids presents major advantages over systemic medication. They can be targeted to the intended site of action, furthermore systemic toxicity is of much lesser concern.

Section: Vascular Resorptionsupporting

confidence: 49%

Section: Vascular Resorptionmentioning

confidence: 99%

Section: Vascular Resorptionmentioning

confidence: 99%

See 1 more Smart Citation

Penetration and Percutaneous Absorption of Topical Retinoids

Schaefer¹

1993

“…Only severe conditions require the use of oral retinoids, in order to induce high systemic concentrations, with the problems of side effects and teratogenic properties that preclude their use for pregnant women [25]. For both cosmetic use and treatments of mild to moderate cutaneous diseases, topical application of retinoids represent a good approach to deliver retinoids directly to the skin; in such cases, systemic concentrations seem to be unaffected [26,27]. However, very few in vivo human studies examining the epidermal concentrations of retinoids following topical application were performed to date [28,29].…”

Section: Discussionmentioning

confidence: 99%

Penetration and Metabolism of Topical Retinoids in ex vivo Organ-Cultured Full-Thickness Human Skin Explants

Antille

Tran

Sorg

et al. 2004

The human epidermis contains endogenous retinoids [retinol (vitamin A) and retinyl esters] and carotenoids (mostly β-carotene). Previous studies in the mouse have shown that the enzymes involved in retinoid metabolism are present in the epidermis. In this study, we wanted to assess the skin penetration and metabolism of topical retinoids in the human. To do this, fresh surgically excised human abdominal skin was mounted on Franz perfusion cells. Topical retinoic acid, retinal, retinol and retinyl palmitate were applied at 2.5 mg/cm² in oil-in-water creams containing 0.05% retinoids on the donor compartment, while the receptor compartment was filled with culture medium. The skin was incubated for 24 h at 37°C, then epidermal retinoid concentrations were determined by HPLC. The same experiment was performed with mouse back skin mounted on Franz cells. Finally, topical retinoids were applied on the back of hairless mice for 24 h; then the mice were sacrificed and retinoid concentrations were assayed in the epidermis. In all three models, retinol and its esters were found to be endogenous, as was the case in previous studies in the mouse in vivo. The four applied retinoids penetrated well into the epidermis. Topical retinoic acid did not increase endogenous retinoids, whereas the latter were greatly increased following topical retinal in the mouse. Retinal was also metabolized into retinoic acid, unlike topical retinol and retinyl palmitate, which only increased endogenous retinoids. Topical retinal and retinol did undergo a higher metabolism in both mouse models than in human skin. In summary, the penetration and metabolism patterns of topical retinoids were quite similar in the two mouse models used, indicating that the Franz cells appear to be a good model to predict in vivo metabolism of topical retinoids. When applying this concept to our results obtained in Franz cells with human skin, we conclude that topical retinol and retinal load human skin with both storage and functional vitamin A.

“…Here, we will not review the extensive literature on this subject, but only discuss recent studies in which parallel toxicokinetic experiments have been performed to provide 38 Nau Embryotoxicity and Teratogenicity of Topical Retinoic Acid the basis for risk assessment of topical alltram-retinoic acid. AUC values will be con sidered here, because they most likely are the appropriate correlates to the teratogenic po tency of active retinoids [3][4][5][6]19].…”

Section: Teratogenicity Of All-trans-retinoic Acid By Other Exposure mentioning

confidence: 99%

Embryotoxicity and Teratogenicity of Topical Retinoic Acid

Nau

1993

All-trans-retinoic acid is a potent developmental toxicant in all species examined. The teratogenic risk of topical all- trans-retinoic acid is reviewed. Experimental studies are limited because of the high maternal toxicity, including skin irritation, with doses below those resulting in significant teratogenic response with other application routes, such as oral application. The maximal systemic availability reported for transdermal exposure of all- trans-retinoic acid was 5-6% in the rat, 9.6% in the monkey (48% with dermatitic skin) and 5-7% in the human. Oral administration of threshold teratogenic doses of all- trans-retinoic acid (6 mg/kg/day) to Wistar rats and Swiss hare rabbits resulted in embryonic area under the concentration time curve levels (approximately 1,000 ng·h/g) which were 2- to 4-fold higher than the endogenous all- trans-retinoic acid levels; corresponding maternal plasma area under the concentration time curve values were 98 and 321 ng·h/ml in rat and rabbit, respectively. The 4-oxo-metab-olite was also found in maternal plasma and embryo. Large, controlled studies on the possible developmental toxicity of topical all- trans -retinoic acid in the human are not available. Isolated case reports appeared in the literature claiming teratogenic outcome resembling effects after oral iso-tretinoin use or those observed in experimental studies with oral or paren-teral all- trans-retinoic acid administration. The dose absorbed from daily cosmetic or therapeutic application of all- trans -retinoic acid is expected to be below 0.015 mg/kg, which is at least 30-fold lower than the lowest teratogenic dose of isotretinoin in the human. Topical all- trans -retinoic acid application did not appreciably alter endogenous plasma retinoid levels. The influence of nutrition, diurnal variation and in particular oral vitamin A supplements are more important determinants of plasma retinoic acid compounds than topical all- trans -retinoic acid. These results imply a low risk of therapeutic or cosmetic application of topical all-trans-retinoic acid. However, the highly specific spatial and temporal distribution of binding proteins and nuclear receptors in the embryo suggests that even small alterations in endogenous levels of all- trans -retinoic acid in the embryo may alter crucial developmental processes such as morphogenes; this aspect should be further investigated.