Debruyne D, Coquerel A
Laboratory of Pharmacology, University Hospital Center, Caen, France.
Clin Pharmacokinet. 2001;40(6):441-72. doi: 10.2165/00003088-200140060-00005.
Onychomycosis is caused by infection by fungi, mainly dermatophytes and nondermatophyte yeasts or moulds; it affects the fingernails and, more frequently, the toenails. Dermatophytes are responsible for about 90 to 95% of fungal infections. Trichophyton rubrum is the most common dermatophyte; Candida albicans is the major nondermatophyte yeast. Although topical therapy of onchomycosis does not lead to systemic adverse effects or interactions with concomitantly taken drugs, it does not provide high cure rates and requires complete compliance from the patient. At present there are 3 oral antifungal medications that are generally used for the short term treatment of onychomycosis: itraconazole, terbinafine and fluconazole. The persistence of these active drugs in nails allows weekly administration, reduced treatment or a pulse regimen. Good clinical and mycological efficacies are obtained with itraconazole 100 to 200 mg daily, terbinafine 250mg daily for 3 months, or fluconazole 150 mg weekly for at least 6 months. Itraconazole is a synthetic triazole with a broad spectrum of action. It is well absorbed when administered orally and can be detected in nails 1 to 2 weeks after the start of therapy. The nail : plasma ratio stabilises at around 1 by week 18 of treatment. Itraconazole is still detectable in nails 27 weeks after stopping administration. Nail concentrations are higher than the minimum inhibitory concentration (MIC) for most dermatophytes and Candida species from the first month of treatment. The elimination half-life of itraconazole from nails is long, ranging from 32 to 147 days. Terbinafine is a synthetic allylamine that is effective against dermatophytes. Terbinafine is well absorbed from the gastrointestinal tract, and the time to reach effective concentrations in nail is 1 to 2 weeks. The half-life is from 24 to 156 days, explaining the observed persistence of terbinafine in nails for longer than 252 days. Fluconazole is a bis-triazole broad spectrum antifungal with high oral bioavailability. The uptake of fluconazole by nail increases with the length of treatment, and nail : plasma ratios are generally 1.5 to 2 at steady state. Fluconazole concentrations exceed the MIC for Candida species soon after the start of treatment. Fluconazole concentrations fall slowly after the drug is stopped, with a half-life of 50 to 87 days, and fluconazole is still detectable in nails 5 months after the end of treatment. All these drugs are potent inhibitors of cytochrome P450 (CYP) enzymes and may increase the plasma concentrations of concomitantly used drugs. Itraconazole inhibits CYP3A4. Fluconazole inhibits CYP3A4, but to a lesser degree than itraconazole, CYP2C9 and CYP2C19. Terbinafine inhibits CYP2D6.
甲癣由真菌感染引起，主要是皮肤癣菌以及非皮肤癣菌的酵母菌或霉菌；它会影响手指甲，更常见的是影响脚趾甲。皮肤癣菌导致约90%至95%的真菌感染。红色毛癣菌是最常见的皮肤癣菌；白色念珠菌是主要的非皮肤癣菌酵母菌。虽然甲癣的局部治疗不会导致全身不良反应或与同时服用的药物发生相互作用，但它的治愈率不高，且需要患者完全依从。目前有3种口服抗真菌药物通常用于甲癣的短期治疗：伊曲康唑、特比萘芬和氟康唑。这些活性药物在指甲中的持续存在使得可以每周给药、缩短治疗时间或采用脉冲疗法。每日服用伊曲康唑100至200毫克、特比萘芬250毫克共3个月或每周服用氟康唑150毫克至少6个月，可获得良好的临床和真菌学疗效。伊曲康唑是一种具有广泛作用谱的合成三唑类药物。口服给药时吸收良好，治疗开始后1至2周可在指甲中检测到。治疗第18周时，指甲与血浆的比例稳定在1左右。停药后27周指甲中仍可检测到伊曲康唑。从治疗的第一个月起，指甲中的浓度就高于大多数皮肤癣菌和念珠菌属的最低抑菌浓度（MIC）。伊曲康唑从指甲中的消除半衰期很长，为32至147天。特比萘芬是一种对皮肤癣菌有效的合成烯丙胺类药物。特比萘芬从胃肠道吸收良好，在指甲中达到有效浓度的时间为1至2周。半衰期为24至156天，这解释了观察到的特比萘芬在指甲中持续存在超过252天的现象。氟康唑是一种具有高口服生物利用度的双三唑类广谱抗真菌药。指甲对氟康唑的摄取随治疗时间延长而增加，稳态时指甲与血浆的比例通常为1.5至2。治疗开始后不久，氟康唑浓度就超过念珠菌属的MIC。停药后氟康唑浓度下降缓慢，半衰期为50至87天，治疗结束后5个月指甲中仍可检测到氟康唑。所有这些药物都是细胞色素P450（CYP）酶的强效抑制剂，可能会增加同时使用药物的血浆浓度。伊曲康唑抑制CYP3A4。氟康唑抑制CYP3A4，但程度低于伊曲康唑，还抑制CYP2C9和CYP2C19。特比萘芬抑制CYP2D6。
