The penetration of daraprim (pyrimethamine) into the monkey eye.

Pyrimethamine (Daraprim) has been ef­ fective in treating acute experimental sys­ temic toxoplasmosis, 1 ' 2 and the work of Ryan 3 and later Perkins 4 suggest that it is of benefit in human ocular disease. Studies by Hogan 5 and Choi 6 on guinea pigs and rabbits raise the possibility, however, that pyri­ methamine may not penetrate into the eye in sufficient quantity to be effective. Further­ more, Choi in his analysis of the concentra­ tion of pyrimethamine in the serum and ocu­ lar tissues of the rabbit, 6 found low concen­ trations of the drug in the serum, and found that although the drug entered the choroid and the iris, the vitreous and the aqueous contained almost no pyrimethamine. Subsequent study of _ the metabolism of pyrimethamine confirms the finding of Hogan that moderate doses of pyrimethamine are not effective in treating uveitis in guinea pigs, but later work by Jacobs, et al. 7 indi­ cates that the reason for this lack of efficacy is that pyrimethamine is poorly absorbed and/or rapidly eliminated by these rodents so that very large doses are required in order to obtain serum or tissue levels comparable to those attained in the human. Cook and Jacobs 11 have established that pyrimethamine has no effect on Toxoplasma in cell-free fluids, but kills the organisms only when they are intracellular and are multiplying. Wilder, Frenkel, and others 8-10 have shown that the primary site of ocular infection by Toxoplasmas in the human is the retina. It appeared desirable, therefore, to determine whether pyrimethamine enters the retina, the tissue in which it must act to be effective. In addition, since a comparison * From the Uveitis Laboratory of the Howe Laboratory of Ophthalmology of the Massachusetts Eye and Ear Infirmary. of the studies of Schmidt 12 and Kaufman 13 indicate that in the monkey, as opposed to many rodents, the metabolism of the drug resembles that of man, it appeared worth­ while to pursue these studies in monkeys. Pyrimethamine concentrations in tissues of the monkey eye are tabulated in the accom­ panying tables. Two Cynemologus monkeys weighing ap­ proximately 13 kg. were given 2.5 mg. of pyrimethamine per kilogram intramuscularly, the drug given to one of the monkeys hav­ ing been radioactively labelled with tritium. Twelve hours after the injection, the animals were killed by exsanguination in order to minimize contamination of the tissues by pyrimethamine …