Kalsi G S, Silver H K, Rootman J
Department of Ophthalmology, University of British Columbia, Vancouver.
Can J Ophthalmol. 1991 Aug;26(5):247-51.
The authors assessed the ocular toxicity and pharmacokinetics of subconjunctivally and intravenously administered dacarbazine in New Zealand white rabbits. Nine rabbits received a subconjunctival injection of 5 mg (three animals), 10 mg (three animals) or 25 mg (three animals) of dacarbazine in 0.5 mL of sterile water; 10 mg was found to be a well-tolerated dose. This dose was given as a bolus to 42 other rabbits either subconjunctivally (21 animals) or intravenously (21 animals). In both groups the dacarbazine concentrations in the ocular humours, serum and urine were measured by means of high-pressure liquid chromatography at 0.5, 1, 2, 4, 8, 12 and 24 hours, three animals being assessed at each interval. The peak serum levels of the drug were similar with the two routes of administration. The mean peak dacarbazine levels in the aqueous humour and vitreous humour after subconjunctival administration were 250 to 380 times those achieved after intravenous administration. The bioavailability of the drug over 24 hours was 107 micrograms/h.mL in the aqueous and 34 micrograms/h.mL in the vitreous after subconjunctival administration, compared with 0.65 and 0.14 micrograms/h.mL respectively after intravenous administration. Our results provide a solid pharmacokinetic basis for considering subconjunctivally administered dacarbazine in the treatment of human ocular melanoma.
作者评估了在新西兰白兔眼内和静脉注射达卡巴嗪后的眼毒性和药代动力学。9只兔子分别接受了结膜下注射0.5 mL无菌水中含5 mg（3只动物）、10 mg（3只动物）或25 mg（3只动物）的达卡巴嗪；发现10 mg是一个耐受性良好的剂量。该剂量以推注方式给予另外42只兔子，其中21只结膜下给药，21只静脉给药。在两组中，分别在0.5、1、2、4、8、12和24小时通过高压液相色谱法测量眼内液、血清和尿液中的达卡巴嗪浓度，每个时间间隔评估3只动物。两种给药途径的药物血清峰值水平相似。结膜下给药后房水和玻璃体液中的达卡巴嗪平均峰值水平是静脉给药后的250至380倍。结膜下给药后24小时药物在房水中的生物利用度为107微克/小时·毫升，在玻璃体液中为34微克/小时·毫升，而静脉给药后分别为0.65和0.14微克/小时·毫升。我们的结果为考虑结膜下注射达卡巴嗪治疗人类眼黑色素瘤提供了坚实的药代动力学基础。
