N-Penicillamine

Dimereaprol, 2,3-dhnercaptosuccinic acid, n-penicillamine Charcoal heraoperfusion, multiple-dose oral activated charcoal, alkaline diuresis (phenobarbital only)... 

Figure 4.1 PMl curves calculated for metal ion-chelating agents bj using computer simulation. PMI is as defined in the text. Ligand symbols Tren — tri-ethylenetetramine EDTA = ethylenediaminetetraacetic acid DTP A = diethylenetriaminepentaacetic acid CDTA = cyclohexylenedijiitrotetra-acetic acid Pen = n-penicillamine OxPen = D-penicillamine-S-S-D-penicillamine, i.e. dimer of Pen BAL = 2,3-dimercaptopropanol DFO = desferrioxamine...

It should be noted, however, that despite the general preference for the marketing of synthetic chiral therapeutic agents in racemic form, a few synthetic chiral drugs were introduced in a unichiral form. Such exceptions included the above-mentioned levodopa and also n-penicillamine 31 [78], (-)-timolol 32 [87], methyl-dopa 33 [88], etc, and it is clear that in most such cases the choice of developing a unichiral form was dictated by overt serious toxicity present predominantly in the ofher enantiomer. 

A study compared the efficacy and side effects associated with n-penicillamine (n=58) versus allicin (n=59) treatment for blood lead concentration in 117 workers [69 ]. The frequency of side effects was significantly higher in patients administered D-penicillamine (250 mg, three times daily) in a study comparing this compound with allicin (1200 gg, three times daily) after 10 days. Both treatments reduced serum lead, but the frequency of side effects was higher in the D-penicillamine group. D-Penicillamine was associated with hypersensitivity (n=5), GI complications (n=6), headache (n=4), somnolence (n = 1), chest pain (n=1) and dizziness (n=1). 

A substantial number of bioactive molecules, such as polypeptides, N-acetyl-DL-penicillamine, p-(dipropylsulfamoyl)benzoic acid, and nicotinic acid, contain a carboxylic acid function, and this provides a site for linkage to a polyphosphazene chain. A number of prototype polymers have been synthesized in which pendent amino groups provide coupling sites for the carboxylic acid (34). The amide linkages so formed are potentially bioerodible, but the use of a hydrolytic sensitizing cosubstituent would be expected to accelerate the process. 

Besada [12] described a spectrophotometric method for determination of penicillamine by reaction with nitrite and Co(II). Penicillamine is first treated with 1 M NaN02 (to convert the amino-group into a hydroxy-group), then with 0.1 M CoCl2, and finally the absorbance of the brownish-yellow complex obtained is measured at 250 nm. The process is carried out in 50% aqueous ethanol, and the pH is adjusted to 5.4— 6.5 for maximum absorbance. The calibration graph is linear over the concentration range of 0.25-2.5 mg per 50 mL, and the mean recovery (n = 3) of added drug is 99.7%. Cystine, cysteine, methionine, and other amino adds do not interfere. 

Al-Ghannam et al. [25] described a simple fluorimetric procedure for determination of three pharmaceutical compounds containing thiol groups, including penicillamine. In this method, the drugs are treated with 1,2-naphthoquinone-4-sulfonic acid. The later compound is reduced to l,2-dihydroxynaphthalene-4-sulfonic acid, which is measured fluorimetrically (excitation = 318 nm, emission = 480 nm). The method is sensitive to 0.5 1.5 pg/mL, with a detection limit of 0.05 pg/mL (S/N = 2). 

Garcia et al. [45] determined penicillamine in pharmaceutical preparations by FIA. Powdered tablets were dissolved in water, and the solution was filtered. Portions (70 pL) of the filtrate were injected into a carrier stream of water that merged with a stream of 1 mM PdCl2 in 1 M HC1 for determination of penicillamine. The mixture was passed though a reaction coil (180 cm long) and the absorbance was measured at 400 nm. Flow rates were 1.2 and 2.2 mL/min for the determination of penicillamine, the calibration graphs were linear for 0.01-0.7 mM, and the relative standard deviation (n = 10) for 0.17 mM analyte was 0.8%. The method was sufficiently selective, and there were no significant differences between the labeled contents and the obtained results. 

Wakabayashi et al. [51] determined penicillamine in serum by HPLC. Serum (0.1 mL) was vortex-mixed for 30 s with 50 pL of 0.1% EDTA and 0.2 mL of 10% TCA. The solution was centrifuged at 1500 x g and filtered. A 5 pL portion was analyzed on a Shodex C18 column (15 cm x 4.6 mm i.d.), using a mobile phase of 19 1 methanolic 0.05 M phosphate buffer (pH 2.8) containing 1 mM sodium octylsulfate and 10 pM EDTA. Liver or kidney samples were similarly extracted, and the extracts were cleaned up on a Bond-Elut cartridge prior to HPLC analysis. Detection was effected with an Eicom WE-3G graphite electrode maintained at +0.9 V versus Ag/AgCl. The calibration graph was linear up to 500 ng, and the detection limits were 20 pg. For 1 pg of penicillamine added to serum, liver, or kidney, the respective relative standard deviations (n = 5) were 3.6, 5.1, and 4.4%. 

The (n)-enantiomer of penicillamine is used clinically in man either as the hydrochloride or as the free amino acid [1], although the (L)-enantiomer also forms chelation complexes. Penicillamine is an effective chelator of copper, mercury, zinc, and lead, and other heavy metals to form stable, soluble complexes that are readily excreted in the urine [2,3]. 

Penicillamine is reported to be more than 80% bound to plasma protein. The compound is metabolized in the liver. N-acetylpenicillamine is more effective than penicillamine in protecting against the toxic effect of mercury, presumably because it is even more resistant to metabolism [7,2]. 

For this method S-nitroso-N-acetyl-D, L-penicillamine (SNAP, FW = 220.3) is decomposed to NO in solution in the presence of a Cu (I) catalyst [77], The resultant NO generated can then be used to calibrate the sensor. The reaction proceeds in accordance to the following reaction ... 

Askew, S., Butler, A., Flitney, F., Kemp, G., Megson, I., Chemical mechanisms underlying the vasodilator and platelet anti-aggregating properties of S-nitroso-N-cetyl-DL-penicillamine and S-nitrosoglutathione, Bioorg. Med. Chem. 3 (1995), p. 1-9... 

Step 3 D-Penicillamine thus obtained is oxidised quantitatively by iodine to give rise to a disulphide, as expressed in the following equation whereas, the excess iodine is back titrated with 0.02 N sodium thiosulphate solution ... 

---