Pharmacokinetics of 2-Mercaptopropionylglycine (Tiopronin) in Patients with Impaired Renal Function

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Abstract

Summary

Ten patients with slight to moderate renal impairment were administered 500mg of tiopronin (2-mercaptopropionylglycine, 2-MPG) orally, and the pharmacokinetics of the drug and the metabolite, 2-mercaptopropionic 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-proteinbound tiopronin were 19 ± 11 and 43 ± 17 L/h (p < 0.01). The peak plasma concentration (Cmax) was greater in the patients but no difference was seen in the time to peak concentration (tmax) [4.4 hours]. Renal clearance (CLR) 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-protein-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 tiopronin) and the fraction of non-protein-bound tiopronin in plasma was somewhat higher in patients but declined in a similar manner to healthy volunteers. The t½γ of tiopronin was 37 hours when calculated using 48-hour data and was found to increase to 70 hours when the terminal phase (i.e. 168-hour data) was taken into account.

Significant pharmacokinetic differences were found between the patients in relation to their 51Cr-EDTA clearance. Thus, patients with moderate renal impairment (51Cr-EDTA clearance about 30 ml/min/1.73m2) had increased half-lives based on the β-phase (t½β) [total tiopronin] and mean residence time (t) [non-protein-bound tiopronin], decreased CL/F and CLR (total and non-protein-bound tiopronin), and decreased Vd/F (total tiopronin) when compared with patients with only slightly decreased renal function. Total urinary recovery of tiopronin in the patients (33%) was the same as in healthy volunteers, although excretion was prolonged in the patients. After 24 hours, excretion was almost complete (97%).

The metabolite 2-MPA had a tmax of about 8 to 9 hours. About 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 administer tiopronin to patients with slight to moderate renal impairment. However, we believe that patients with a 51Cr-EDTA clearance of less than 30 ml/min/1.73m2 should be closely monitored during tiopronin treatment until further investigations have been carried out.

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