The steady-state pharmacokinetics of tiopronin (2-mercaptopropionylglycine, 2-MPG), were studied in healthy volunteers after single (n = 10) and multiple (n = 7) oral doses. Similarly, 5 patients with cystinuria on maintenance doses of tiopronin were studied. The pharmacokinetics of tiopronin in the healthy volunteers did not differ significantly during 10 days of treatment, i.e. the area under the concentration-time curve, time to reach maximum plasma concentration, apparent oral clearance (CL/F), renal clearance (CLR), terminal elimination half-life (t½), and amount of dose excreted in urine were similar. The apparent volume of distribution (Vd/F) was, however, different and might have been due to altered plasma and tissue binding after multiple doses. The pharmacokinetics of tiopronin after multiple oral doses in healthy volunteers compared with maintenance doses in patients with cystinuria were generally the same. The terminal t½of total tiopronin was somewhat longer owing to firm protein and tissue binding. The decreased CL/F and CLRfound in the patients with cystinuria were probably a consequence of decreased glomerular filtration rate (51Cr-EDTA clearance) in this group. No differences in the pharmacokinetics of the metabolite 2-mercaptopropionic acid (2-MPA) were found between the 2 groups. The effects of tiopronin on cystine excretion in patients with cystinuria were confined to the first 12 hours after administration.We conclude that the pharmacokinetics of tiopronin were similar after single and multiple doses in healthy volunteers. At steady-state no major differences in the pharmacokinetics of tiopronin and 2-MPA were found between healthy volunteers after 10 days of treatment and patients with cystinuria on maintenance doses. The rapid decrease in cystine excretion after a single dose of tiopronin and the fast elimination of the active form (non-protein-bound) of the drug implies that the drug should be administered more often than the long terminal t½of total tiopronin suggests, because it does not seem to accumulate in the body. Thus, we propose that tiopronin should be given in divided doses, at least twice daily, for optimal efficacy in the treatment of cystinuria.