The Interaction of thiol drugs and urine pH in the treatment of cystinuria.

Pharmacological therapy for cystinuria consists of alkali salts to increase urine pH and thiol drugs to form soluble cysteine-drug complexes. The effect of alkalinizing urine on thiol drug activity has not been well studied. Urine samples were obtained from 5 healthy subjects and pH was adjusted (range 6.0 to 8.0) in each urine aliquot. Urine samples were incubated with cystine crystals at 37C for 5, 15 and 60 minutes, and 48 hours. We compared cystine solubility in urine samples spiked with thiol drugs at a final concentration of 2 mM to that in control urine samples at the various pH levels and time points. In samples incubated for 48 hours, which is the standard time frame for solubility studies, cystine solubility more than doubled with thiol drugs compared to control and did not depend on pH. However, when incubation time was shortened to 5 minutes, representing the dwell time of urine in the renal pelvis, the effect of thiol drugs to solubilize cystine greatly depended on urine pH with less cystine dissolved at lower pH. Increasing urine pH greatly increased the efficacy of thiol drugs to solubilize cystine in a clinically relevant time frame. These findings suggest that to maximize the benefit of thiol drugs alkali therapy should be used in conjunction with thiol drugs with the goal of keeping urine pH at 7.5 or above. Clinical trials are needed to confirm these in vitro findings.