OCULAR PHARMACOKINETICS OF DACARBAZINE FOLLOWING SUBCONJUNCTIVAL VERSUS INTRAVENOUS ADMINISTRATION IN THE RABBIT

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-mu-g/h.mL in the aqueous and 34-mu-g/h.mL in the vitreous after subconjunctival administration, compared with 0.65 and 0.14-mu-g/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.