| Biological half-life of drug: |
Tiopronin (Acadione) after oral administration of 500mg tablet:
The plasma concentration of tiopronin fell biexponentially with half-lives of about 2.4 and 15-30 hrs. the mean residence time found to be 11hrs
The elimination of 2-MPG was monoexponential with half-life of 4-12hrs. the mean residence time found to be 15-22hrs[1].
Tiopronin (Thiola) after oral administration of 500mg tablet in volunteers fasting since 6-8hrs:
After shorter beta phase, a long terminal half life of 53h 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)[2].
2-MPG after single iv injection of 250mg tablet in volunteers(10) fasting overnight:
The total and non-protein-bound 2-MPG showed terminal half-lives of 55 and 59 h respectively. The proportion of non-protein-bound 2-MPG diminished exponentially during the first 15 h and then levelled off at about 30%. There was a nonlinear increase in the non-protein-bound fraction of 2-MPG as the total plasma concentration of the drug increased [3].
Tiopronin 750mg orally daily for 10 days in healthy volunteers(Group1) and in cystinuria patients(Group2):
The terminal half-life of total tiopronin was longer owing to firm protein and tissue binding in Group 1 [4].
Single oral dose of 400mg tiopronin to 5 healthy volunteers:
Elimination from blood was rapid with half-life of 1.2 hr[5].
Differences in the pharmacokinetic parameters between (-)-tiopronin and (+)-tiopronin were reported after iv administration of racemic-tiopronin
in rats[6].
|
| Peak Seum/Plasma drug level in man: |
Tiopronin (Acadione) after oral administration of 500mg tablet: Cmax 3-4µg/ml at a tmax of 4-6hr after a lag time of about 0.5 hr
2-MPA: tmax of 10-12 hr after a lag time of about 3 hr[1].
Tiopronin (Thiola) after oral administration of 500mg tablet in volunteers fasting since 6-8hrs: tmax 3-6hrs.
Extensive protein binding in plasma and a deep pool of tissue bound tiopronin after the first absorption and distribution phases [2].
Tiopronin 750mg orally daily for 10 days in healthy volunteers(Group1) and in cystinuria patients(Group2):
Tiopronin rapidly forms disulphides with both proteins and low molecular weight thiols[4].
single oral dose of 400 mg tiopronin to five healthy volunteers:
Tiopronin appeared in the blood with a maximum concentration of 2.6 μg mL−1 and peaked at 1.1 h [5].
Tiopronin enteric capsules(500 mg single dose oral administration):
Tmax was 5h, Cmax is 3.6yg/ml. plasma protein binding is approximately 49%[7].
|
| Plasma/serum constituent binding/Protein Binding: |
|
| Drug Tumor level: |
|
| Drug Diffusion in tumor |
|
| Uptake/Distribution of Drug: |
Data from Healthy volunteers oral administration of 500mg Acadione tablets :
The absorption in intestine was slow[1].
Tiopronin enteric capsules(500 mg single dose oral administration):
tiopronin easily absorbed in the intestine, the bioavailability is 85% to 90% [7] and rapidly formed various disulfide forms
[1].
tiopronin is unlikely to cross the blood brain barrier to any significant extent[8].
It can cross the cell membrane[9].
MPG displayed a marked affinity for red cells in vitro and penetrated them without an incubation period [10].
|
| Pathway: |
Possible route for metaboism of 2-MPG:
2-MPG on moderat oxidation produces symmetrical, asymmetrical disulphide bond structure, and upon strong oxidation produces sulphoxide, sulphone etc. 2-MPG hydrolyses to 2-MPA, which upon moderate oxidation produces disulphide bond structure and upon strong oxidation, produces sulphoxide and sulphone[1]
|
| Biotransformation Location: |
tiopronin enteric capsule is metabolized in liver [7].
|
| drug metabolite: |
Principle metabolite 2-mercaptopropionic acid(2-MPA) [107-11]after oral administration of 500mg of 2-MPG tablet(Acadione) in healthy volunteers
(About 15% of the tiopronin found to be metabolized to 2-MPA)[1].
After rapid absorprion in gastrointestinal tract it rapidly oxidizes to various disulfide forms
[12],[1] or as a mixed forms with endogenous thiols[13].
In biological fluid, Tiopronin can exist as several molecular species including free thiol
(T-SH), symmetrical disulfide (T-S-S-T), mixed disulfide with another low molecular thiols(T-S-S-R) and mixed disulphide with proteins
bearing free thiol group(T-S-S-P)[14].
|
| Associated Enzymes/receptors: |
A strong competitive inhibitory effect of tiopronin on the multienzyme redox system hemoglobin, nicotinamide adenine dinucleotide (NADH) and H2O2
has been observed [15].
Tiopronin suppressed the decrease in Aniline hydroxylating enzyme activity and aminopyrine N-demethylating enzyme activity of the liver microsome
of rats[16]; however another study showed inhibition of aminopyrine N-demethylase by 2-MPG. MPG not only increased the Km value for
aminopyrine N-demethylase but also the apparent Ks value for aminopyrine binding to the microsomal oxidized cytochrome P-450 by interacting with the
cytochrome P-450[17].
tiopronin, and number of structurally related analogs are substrates or inhibitors of peptidylglycine alpha-amidating monooxygenase (PAM) with Kd
values < 100µM [8].
2-MPG activated Cu, Zn-superoxide dismutase purified from rat liver at low conc. (below 10µM) by reducing Cu+2 present in catalytic site of the
dismutase [18].
|
| Transporters/Carriers: |
Tiopronin was found to be selectively toxic to the drug efflux pumps p-glycoprotein (P-gp, ABCB 1)
and MRP-1(ABCC 1) [19].
Tiopronin does not inhibit the activity of ABC transporters, thereby reducing the chance of undesired side- effects during treatment.
The effects of Tiopronin correlates with the level of ABC transporter expression, allowing healthy cells to better survive
treatments.[20].
|
| Route of Elimination: |
Through urine[2],[3],[4], [5] |
| Excretion/Clearance: |
Tiopronin (Thiola) after oral administration of 500mg tablet in volunteers fasting since 6-8 hrs:
Urinary excretion was mainly confined to the first 6 h (74%) and was almost complete (98%) within 12 h. The renal excretion of low molecular weight
tiopronin occurred early[2].
2-MPG after iv administration of 250mg tablet in volunteers fasting overnight:
75% of the dose was excreted in the urine, mainly during the first 6 h after injection[3].
Tiopronin 750mg orally daily for 10 days in healthy volunteers(Group1) and in cystinuria patients(Group2):
Plasma non-protein bound tiopronin has a shorter elimination half-life[4].
single oral dose of 400 mg tiopronin to five healthy volunteers:
Tiopronin (15.5% dose) and its mixed disulphides (33.9% dose) were excreted in urine within 8 h.[5].
|
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