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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].
1. Hercelin B, Leroy P, Nicolas A, Gavriloff C, Chassard D, Thébault JJ, Reveillaud MT, Salles MF, Netter P., The pharmacokinetics of tiopronin and its principal metabolite (2-mercaptopropionic acid) after oral administration to healthy volunteers, Eur J Clin Pharmacol. 1992; 43(1):93-5.
2. Carlsson MS, Denneberg T, Emanuelsson BM, Kågedal B, Lindgren S., Pharmacokinetics of oral tiopronin, Eur J Clin Pharmacol. 1993; 45(1):79-84.
3. Carlsson SM, Denneberg T, Emanuelsson BM, Kågedal B, Lindgren S, Pharmacokinetics of intravenous 2-mercaptopropionylglycine in man, Eur J Clin Pharmacol. 1990; 38(5):499-503.
4. Carlsson MS , Denneberg Torsten , Emanuelsson Britt-Marie , Kågedal B , Lindgren S , Steady-State Pharmacokinetics of 2-Mercaptopropionylglycine (Tiopronin) in Healthy Volunteers and Patients with Cystinuria, 1994; 7(1):41-51.
5. Matsuura K, Shidawara S, Mano H, Irino T , Takashina H, Pharmacokinetics of Tiopronin after Oral Administration in Healthy Volunteers, Pharmacy and Pharmacology Communications 1999;5(5): 345–347.
6. Wang Huan,Chen Yuan-cheng,Ma Chen,Zhou Jia,Liu Xiao-quan, Stereoselective pharmacokinetics of tiopronin enantiomers in rats, Journal of China Pharmaceutical University, 2008-01.
7. Li Xiaodong, Lu Xi Ming, Lu Wenjuan, Applicant- Pharmaceutical Co., Ltd., Suzhou two leaves, Tiopronin enteric capsule prescription and preparation process thereof, 2012, publication number CN 102552207 A, Google patent.
8. McIntyre NR, Lowe EW Jr, Chew GH, Owen TC, Merkler DJ, Thiorphan, tiopronin, and related analogs as substrates and inhibitors of peptidylglycine alpha-amidating monooxygenase (PAM), FEBS Lett. 2006; 580(2):521-32.
9. Myers ML, Bolli R, Lekich RF, Hartley CJ, Roberts R, N-2-mercaptopropionylglycine improves recovery of myocardial function after reversible regional ischemia, J Am Coll Cardiol. 1986; 8(5):1161-8.
10. Germano D, Abbate C, Granata A, Erythrocyte protective synergism of ascorbic acid and alphamercaptopropionylglycine, Minerva Med. 1979;70(38):2615-9.
11. Mrtensson J, Denneberg T, Kgedal B, 2-Mercaptopropionate, a novel metabolite formed during treatment with 2-mercaptopropionyl-glycine in cystinuria, Eur J Clin Pharmacol. 1986; 31(1):119-21.
12. Kusmierek K, Bald E, Simultaneous determination of tiopronin and d-penicillamine in human urine by liquid chromatography with ultraviolet detection, Anal Chim Acta. 2007; 590(1):132-7.
13. Ma J, Gu Y, Chen B, Yao S, Chen Z, High-performance liquid chromatography-electronspray ionization mass spectrometry for determination of tiopronin in human plasma, J Chromatogr A. 2006;1113(1-2):55-9.
14. Liu J, Wu H, Hou Y, Determination of total tiopronin in human plasma by LCESIMS using tris (2-carboxy-ethyl) phosphine as reducing reagent and methyl acrylate as derivatization reagent for the thiol group, J Chromatogr B Analyt Technol Biomed Life Sci. 2006 ;844(1):153-7.
15. Xu J, Cai R, Wang J, Liu Z, Wu X, Fluorometric assay of tiopronin based on inhibition of multienzyme redox system, J Pharm Biomed Anal. 2005; 39(1-2):334-8.
16. Chiba T, Horiuchi M, Akashi Y, Effect of thiol compounds on experimental liver damage (III). Effect of tiopronin (2-mercaptopropionylglycine) and glutathione on drug metabolizing activity (author's transl), Nihon Yakurigaku Zasshi. 1979; 75(6):563-70.
17. Harata J, Nagata M, Ishiguro I, Ohta Y, Effect of 2-mercaptopropionylglycine on lipid peroxidation and drug oxidation in rat liver microsomes, Biochem Int. 1984;8(1):49-59.
18. Hoshino T, Ohta Y, Ishiguro I, The effect of sulfhydryl compounds on the catalytic activity of Cu, Znsuperoxide dismutase purified from rat liver, Experientia. 1985; 41(11):1416-9.
19. Goldsborough AS, Handley MD, Dulcey AE, Pluchino KM, Kannan P, Brimacombe KR, Hall MD, Griffiths G, Gottesman MM., Collateral sensitivity of multidrug-resistant cells to the orphan drug tiopronin, J Med Chem. 2011;54(14):4987-97.
20. Authenticated US Government Information, Federal Register/Vol. 76, No. 54/Monday, March 21, 2011/Notices, page 15328.