PHARMACOKINETICS OF 2-MERCAPTOPROPIONYLGLYCINE (TIOPRONIN) IN PATIENTS WITH IMPAIRED RENAL-FUNCTION

Ten patients with slight to moderate renal impairment were administere d 500mg of tiopronin (2-mercaptopropionylglycine, 2-MPG) orally, and t he pharmacokinetics of the drug and the metabolite, 2-mercaptopropioni c acid (2-MPA), were evaluated and compared with previous results from 10 healthy volunteers. Total clearance (CL/F) of tiopronin in the 10 patients was estimated at 6.8 +/- 2.8 L/h compared with 10.2 +/- 2.7 L /h (p < 0.05) in healthy volunteers. The corresponding values for non- protein-bound tiopronin were 19 +/- 11 and 43 +/- 17 L/h (p < 0.01). T he peak plasma concentration (C-max) was greater in the patients but n o difference was seen in the time to peak concentration (t(max)) [4.4 hours]. Renal clearance (CL(R)) estimated from total plasma tiopronin was 2.7 +/- 1.0 and 6.5 +/- 1.2 L/h in patients and healthy volunteers , respectively (p < 0.01), and the corresponding values for non-protei n-bound tiopronin were 5.4 +/- 2.5 and 13.3 +/- 2.0 L/h, respectively. Volume of distribution (Vd/F) was reduced in patients (4.5 +/- 1.8 L/ kg for total tiopronin and 0.9 +/- 0.4 L/kg for non-protein-bound tiop ronin) and the fraction of non-protein-bound tiopronin in plasma was s omewhat higher in patients but declined in a similar manner to healthy volunteers. The t(1/2 gamma) of tiopronin was 37 hours when calculate d using 48-hour data and was found to increase to 70 hours when the te rminal phase (i.e. 168-hour data) was taken into account. Significant pharmacokinetic differences were found between the patients in relatio n to their Cr-51-EDTA clearance. Thus, patients with moderate renal im pairment (Cr-51-EDTA clearance about 30 ml/min/1.73m(2)) had increased half-lives based on the beta-phase (t(1/2 beta)) [total tiopronin] an d mean residence time (t) [non-protein-bound tiopronin], decreased CL/ F and CL(R) (total and nonprotein-bound tiopronin), and decreased Vd/F (total tiopronin) when compared with patients with only slightly decr eased renal function. Total urinary recovery of tiopronin in the patie nts (33%) was the same as in healthy volunteers, although excretion wa s prolonged in the patients. After 24 hours, excretion was almost comp lete (97%). The metabolite 2-MPA had a t(max) of about 8 to 9 hours. A bout 14% of tiopronin was metabolised to 2-MPA and only small amounts of 2-MPA (2%) were found in urine. It therefore appears safe to admini ster tiopronin to patients with slight to moderate renal impairment. H owever, we believe that patients with a Cr-51-EDTA clearance of less t han 30 ml/min/1.73m(2) should be closely monitored during tiopronin tr eatment until further investigations have been carried out.