Goldblum David, Fausch Kathrin, Frueh Beatrice E, Theurillat Regula, Thormann Wolfgang, Zimmerli Stefan
Clinic of Ophthalmology, University Hospital, Inselspital, 3010, Bern, Switzerland.
Graefes Arch Clin Exp Ophthalmol. 2007 Jun;245(6):825-33. doi: 10.1007/s00417-006-0460-x. Epub 2006 Nov 22.
Little is known about the ocular penetration of echinocandin antifungals. We studied the ocular distribution of systemically administered caspofungin in a rabbit uveitis model.
Caspofungin (1 mg/kg per day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7 days starting 24 h after induction of unilateral uveitis by intravitreal endotoxin injection. Caspofungin concentrations were determined by high-performance liquid chromatography in the cornea, aqueous humor, vitreous humor, and serum 4, 8, 16, and 24 h after administration of a single dose and 24 h after the last of seven doses.
The mean caspofungin concentration in the aqueous of the inflamed eye 4 and 8 h after single-dose administration was 1.30 +/- 0.39 microg/ml and 1.12 +/- 0.34 microg/ml, respectively. Drug concentrations decreased to 0.24 +/- 0.09 microg/ml at 16 h and 0.26 +/- 0.14 microg/ml at 24 h. In the vitreous of inflamed eyes drug levels were undetectable at all time points. No drug was found in the aqueous of inflamed eyes 24 h after the last of seven repeated doses, and the vitreous only contained trace amounts. In the corneas of inflamed eyes concentrations reached 1.64 +/- 0.48 microg/g at 4 h, peaked at 2.16 +/- 1.14 microg/g at 8 h, and declined to 1.87 +/- 0.52 microg/g and 1.49 +/- 0.48 microg/g at 16 and 24 h, respectively. After repeated dosing, corneal concentrations of caspofungin were 0.8 and 1.0 microg/g and below the limit of detection in two of four animals. In non-inflamed eyes no drug was detectable in the aqueous and vitreous humor, and the corneas at any time point.
In our model, caspofungin reached therapeutically relevant levels in the aqueous and cornea but not in the vitreous humor of inflamed eyes. Intraocular drug deposition was critically dependent on a disrupted blood-eye barrier. These findings suggest a limited role for caspofungin in the treatment of fungal endophthalmitis.
棘白菌素类抗真菌药的眼内穿透情况鲜为人知。我们在兔葡萄膜炎模型中研究了全身给药的卡泊芬净的眼内分布。
通过玻璃体内注射内毒素诱导单侧葡萄膜炎24小时后，以单剂量或连续7天每日重复剂量静脉给予兔卡泊芬净（1毫克/千克/天）。在单次给药后4、8、16和24小时以及七次剂量中的最后一次给药后24小时，通过高效液相色谱法测定角膜、房水、玻璃体和血清中的卡泊芬净浓度。
单剂量给药后4小时和8小时，患眼房水中卡泊芬净的平均浓度分别为1.30±0.39微克/毫升和1.12±0.34微克/毫升。药物浓度在16小时降至0.24±0.09微克/毫升，在24小时降至0.26±0.14微克/毫升。在患眼玻璃体中，所有时间点均未检测到药物水平。在七次重复给药中的最后一次给药后24小时，患眼房水中未发现药物，玻璃体中仅含有痕量药物。在患眼角膜中，浓度在4小时达到1.64±0.48微克/克，在8小时达到峰值2.16±1.14微克/克，在16小时和24小时分别降至1.87±0.52微克/克和1.49±0.48微克/克。重复给药后，四只动物中有两只动物角膜中卡泊芬净的浓度分别为0.8和1.0微克/克，低于检测限。在非患眼中，房水、玻璃体和角膜在任何时间点均未检测到药物。
在我们的模型中，卡泊芬净在患眼的房水和角膜中达到了治疗相关水平，但在玻璃体中未达到。眼内药物沉积严重依赖于受损的血眼屏障。这些发现表明卡泊芬净在真菌性眼内炎治疗中的作用有限。
