Pharmacokinetics of oral tiopronin

Abstract

Ten healthy subjects were given 500 mg (3064 mumol) tiopronin, or 2-mercaptopropionylglycine (2-MPG) by mouth. Cmax was reached after 3-6 h, and after a shorter beta-phase a long terminal half-life of 53 h of total tiopronin was found. Tiopronin measured as unbound (non-protein-bound) drug disappeared more rapidly from plasma, with a calculated t1/2 of 1.8 h. Mean residence time was higher (58 h) when calculated as total tiopronin than as unbound tiopronin (6 h), and this was also the case for the volume of distribution (V lambda = 455 l vs V lambda,u = 41 l). The results indicate extensive protein binding in plasma and a deep pool of tissue bound tiopronin after the first absorption and distribution phases. Absolute bioavailability (f) was 63%, and bioavailability calculated from urinary excretion was 47%, which are well correlated with each other. Urinary excretion was mainly confined to the first 6 h (74%) and was almost complete (98%) within 12 h. We conclude that the maximal absorption of the tiopronin was late, protein and tissue binding of the drug were high and its bioavailability varied. The renal excretion of low molecular weight tiopronin occurred early, which implies that the drug should be given in divided doses, at least twice daily, for optimal efficiency in the treatment of cystinuria.

Urinary Excretion of Free Cystine and the Tiopronin-Cysteine-Mixed Disulfide during Long-Term Tiopronin Treatment of Cystinuria

“…Cystine precipitation, how ever, depends on the prevailing cystine concentration which presumably varies with diuresis, and which is not reflected by 24-hour samples. Recent pharmacokinetic results also indicate that tiopronin should be given in at least two divided doses [15][16][17], Long-term treatment with tiopronin in cystinuria is effective from a biochemical point of view, tiopronin should be given in divided doses, and in order to optimize the treatment in the individual patient regular measure ments of urinary cystine concentration are required.…”

“…Well-founded recommendations for the dosage of tiopronin have been lacking. Recently, however, the pharmacokinetics were elucidated, and the results indicated that the drug should be given in at least two divided doses [15][16][17], Difficulties exist in evaluating the effects of preventive treatment in patients with renal stone diseases. Exacerba tions of stone formation occur irregularly, the interpreta tion of clinical symptoms is unreliable, and the time at which stone passages or colic pain occur are not likely to be closely related to the time of stone formation.…”

The pharmacokinetics of tiopronin as such is unknown

“…Thus, in plasma a decreasing proportion of non-protein-bound [(a + b)/(a + b + c)] tiopronin was found with time after iv [4] or oral [5] administration, i. e. the relative protein binding of tiopronin increased with time after intake. Once established, the protein-binding of tiopronin in plasma is quite strong, and chemical reduction is required to split the bond and so to release the drug from proteins [1,2].…”

“…Once the low-molecular weight species of tiopronin have mainly disappeared from plasma, the amount remaining corresponds to protein-bound tiopronin and a (low-molecular weight) fraction released from tissue to plasma. This occurs after about 12 h ( [4,5], and, assuming similar pharmacokinetics of all possible protein-bound tiopronin molecular species, we estimated the tl/2 of the terminal phase. This phase is very slow and strong tissue binding may be the reason for the very high (virtual) distribution volume.…”

The Molecular Basis of Cystinuria

“…In 1968, King [33]showed that another sulfur-containing agent, α-mercaptopropionyl glycine (MPG), could also form soluble mixed disulfides with cystine in the urine. Most (74%) of the drug is excreted within 6 h of oral administration, implying an optimal dosing regimen of every 6–8 h [34]. Doses from 10 to 30 mg/kg/day have been used to bring free urinary cystine below the theoretic threshold of 1,200 µmol/l [24, 35].…”