Orfanos C E, Zouboulis C C
Department of Dermatology, University Medical Center Benjamin Franklin, Free University of Berlin, Germany.
Dermatology. 1998;196(1):140-7. doi: 10.1159/000017848.
Isotretinoin is an extremely effective drug if given systemically in severe forms of seborrhoea and acne, being the only retinoid with potent sebostatic properties. Its unique activity on the sebaceous gland still remains unclear since isotretinoin barely binds to cellular retinoic-acid-binding proteins and to retinoic acid receptors. Its bioavailability is approximately 25% and can be increased by food 1.5-2 times; after 30 min, the drug is detectable in the blood and maximal concentrations are reached 2-4 h after oral intake. The major metabolites of isotretinoin in blood are 4-hydroxy- and 4-oxo-isotretinoin, while several glucuronides are detectable in the bile. 4-Oxo-isotretinoin is present in plasma in a 2- to 4-fold higher concentration 6 h after a single dose. Steady-state concentrations appear after 1 week. The half-life elimination rate of the parent compound ranges from 7 to 37 h while that of some metabolites does so from 11 to 50 h. Isotretinoin crosses the placenta and is recognized as a strong teratogenic compound. About 10-30% of the drug is metabolized via its isomer tretinoin. Excretion of isotretinoin occurs after conjugation with the faeces or after metabolization with the urine. The epidermal levels of isotretinoin are rather low and no progressive accumulation, either in serum or in the skin, is found. After discontinuation of therapy, isotretinoin disappears from serum and skin within 2-4 weeks. Isotretinoin is the most effective drug in reducing sebaceous gland size (up to 90%) by decreasing proliferation of basal sebocytes, suppressing sebum production and inhibiting sebocyte differentiation in vivo. The molecular basis for its antisebotrophic activity has not been fully elucidated. Isotretinoin also exhibits anti-inflammatory activities. Systemic isotretinoin is today the regimen of choice in severe seborrhoea, since it reduces sebocyte lipid synthesis by 75% with daily doses as low as 0.1 mg/kg after 4 weeks. Patients who have received oral isotretinoin therapy for seborrhoea do not usually experience a relapse for months or years. In severe acne, a 6- to 12-month treatment with isotretinoin 1 mg/kg/day reduced to 0.5 or 0.2 mg/kg/day according to the response is recommended (cumulative dose of > 120 mg/kg). Contraception is essential during isotretinoin treatment in women of childbearing age 1 month before, during and for 3 months after discontinuation of treatment.
异维A酸若全身给药用于重度脂溢性皮炎和痤疮，是一种极其有效的药物，是唯一具有强效抑制皮脂分泌特性的维甲酸类药物。由于异维A酸几乎不与细胞视黄酸结合蛋白和视黄酸受体结合，其对皮脂腺的独特作用仍不清楚。其生物利用度约为25%，食物可使其提高1.5 - 2倍；30分钟后，药物可在血液中检测到，口服后2 - 4小时达到最大浓度。异维A酸在血液中的主要代谢产物是4 - 羟基 - 和4 - 氧代 - 异维A酸，而在胆汁中可检测到几种葡萄糖醛酸苷。单次给药6小时后，4 - 氧代 - 异维A酸在血浆中的浓度高出2至4倍。1周后出现稳态浓度。母体化合物的半衰期消除率为7至37小时，而一些代谢产物的半衰期消除率为11至50小时。异维A酸可穿过胎盘，被认为是一种强致畸化合物。约10 - 30%的药物通过其异构体维甲酸代谢。异维A酸在与粪便结合或经尿液代谢后排出。异维A酸在表皮中的水平相当低，在血清或皮肤中均未发现渐进性蓄积。治疗中断后，异维A酸在2 - 4周内从血清和皮肤中消失。异维A酸是通过减少基底皮脂腺细胞增殖、抑制皮脂分泌和抑制皮脂腺细胞分化来减少皮脂腺大小（高达90%）的最有效药物。其抗皮脂分泌活性的分子基础尚未完全阐明。异维A酸还具有抗炎活性。如今，全身应用异维A酸是重度脂溢性皮炎的首选治疗方案，因为每日剂量低至0.1mg/kg，4周后可使皮脂腺细胞脂质合成减少75%。接受口服异维A酸治疗脂溢性皮炎的患者通常数月或数年不会复发。在重度痤疮中，建议使用异维A酸1mg/kg/天治疗6至12个月，根据反应减至0.5或0.2mg/kg/天（累积剂量>120mg/kg）。育龄期女性在异维A酸治疗前1个月、治疗期间及停药后3个月必须采取避孕措施。
