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2-mercaptopropionylglycine

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PHARMACOLOGICAL ASPECTS

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].
REFERENCES
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.
http://dx.doi.org/10.1007/BF02280762
2. Carlsson MS, Denneberg T, Emanuelsson BM, Kågedal B, Lindgren S., Pharmacokinetics of oral tiopronin, Eur J Clin Pharmacol. 1993; 45(1):79-84.
http://dx.doi.org/10.1007/BF00315354
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.
http://dx.doi.org/10.1007/BF02336691
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.
http://dx.doi.org/10.1007/BF03257398
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.
http://onlinelibrary.wiley.com/doi/10.1211/146080899128734947/abstract
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.
http://en.cnki.com.cn/Article_en/CJFDTOTAL-ZGYD200801023.htm
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.
https://www.google.com/?tbm=pts#q=CN+102552207+A&tbm=pts
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.
http://dx.doi.org/10.1016/j.febslet.2005.12.058
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.
http://dx.doi.org/10.1016/S0735-1097(86)80396-5
10. Germano D, Abbate C, Granata A, Erythrocyte protective synergism of ascorbic acid and alphamercaptopropionylglycine, Minerva Med. 1979;70(38):2615-9.
http://www.ncbi.nlm.nih.gov/pubmed/481785
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.
http:/dx.doi.org/10.1007/BF00871000
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.
http://dx.doi.org/10.1016/j.aca.2007.03.025
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.
http://dx.doi.org/10.1016/j.chroma.2006.01.114
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.
http://dx.doi.org/10.1016/j.jchromb.2006.06.035
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.
http://dx.doi.org/10.1016/j.jpba.2005.03.004
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.
http://www.ncbi.nlm.nih.gov/pubmed/120298
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.
http://www.ncbi.nlm.nih.gov/pubmed/6477598
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.
http:/dx.doi.org/10.1007/BF01950012
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.
http://pubs.acs.org/doi/ipdf/10.1021/jm2001663
20. Authenticated US Government Information, Federal Register/Vol. 76, No. 54/Monday, March 21, 2011/Notices, page 15328.
http://www.gpo.gov/fdsys/pkg/FR-2011-03-21/pdf/FR-2011-03-21.pdf