Enhanced Solubility of 2,8 Dihydroxyadenine (DOA) in Human Urine

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Abstract
Water solubility of the adenine catabolite 2,8 dihydroxyadenine (DOA) frequently forms the basis for predicting potential DOA crystal formation in human urine following infusion of adenine-fortified blood. Measurements relevant to solubility, ionic dissociation, and supersaturability of DOA in aqueous buffers and human urine at 37 C establish striking quantitative differences in the physico-chemical behavior of DOA in the two media. The basal solubility of DOA is 1.53 + 0.04 mg/1 (≅9 times 10-6 M) in water (pH 6.5). DOA is an ampholyte characterized by aqueous thermodynamic macrodissociation constants of pKa1= 2.6, pKa2= 8.1, and pKa3= 11.52. This compound displays pH-dependent solubility, although significant solubility increases beyond basal values do not occur within the physiologic pH range for human urine. Supersaturated aqueous solutions (three to sixteen times basal solubility) can be achieved but are unstable. In contrast, human urine at 37 C exhibits enhanced capacity for solubilizing DOA. In vitro basal solubility is 2.68 + 0.84 mg/l at pH 5.0 and 4.97 + 1.49 mg/l at pH 7.8. The apparent pK2 for DOA in urine of 7.9 to 8.1 is dependent upon urine osmolality. Urine can be supersaturated with DOA in vitro to approximately ten times its basal solubility by adding DOA solubilized in weak base, or by evaporation of a urine-DOA mixture. DOA remains supersaturated in urine for at least 16 hours despite gentle agitation. Little variation in in vitro DOA apparent supersaturation was found among urine samples from four normal individuals (40.38 + 3.33 mg/l). A patient receiving oral adenine exhibited urinary DOA solubility in considerable excess (96.0 mg/l) of that predicted from water and from in vitro urine solubility studies. Thus, water solubility of DOA is poorly predictive of in vitro and in vivo DOA solubility in human urine. On the basis of these data, estimates of the load of adenine-fortified blood expected to result in urinary DOA crystal formation may be revised upward.

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