Chlorpromazine oxidation

Is chlorpromazine oxidized or reduced at the graphite working electrode ... 

The phenothiazines, chlorpromazine and promethazine, have been described as inhibitors of CCU-induced lipid peroxidation at relatively high concentrations in rat liver microsomes (Slater, 1968). Structural modifications of chlorpromazine were undertaken to try to increase antioxidant activity and maintain molecular lipophilicity. The 2-N-N-dimethyl ethanamine methanesulphonate-substituted phenothiazine (3) was found to be a potent inhibitor of iron-dependent lipid peroxidation. It was also found to block Cu -catalysed oxidation of LDL more effectively than probucol and to protect primary cultures of rat hippocampal neurons against hydrogen peroxide-induced toxicity in vitro (Yu et al., 1992). 

Other important aromatic amines such as chlorpromazine (26) have also been subjected to oxidation studies using oxidants produced by pulse radiolysis. Typical among these is the use of chloroalkylperoxyl radicals formed by pulse radiolysis in a variety of solvents. These oxidants yield the corresponding radical cation. The rate constants (Table 3) for these reactions were determined42. Other studies have determined the reactivity between chlorpromazine and BiV- in H2O/DMSO in varying proportions. The rate constants for the formation of the radical cation of chlorpromazine were similar in value to those obtained from the peroxy radical reactions4. 

Chloropentammine Ir (HI) complex, incomplete Ir (III) autoreduction, 39 151-152 Chloroplasts, quantum conversion in, 14 1 1 -Chloroprop-2-ene thermal decomposition, 41 80 Chlorpromazine, reactivity with EDA complexes, 20 333, 336 CH O, 32 374-375 CH3OH, oxidation, 38 21-23 Cholestenone, hydrogenation, 25 57, 58 Cholesterol, biosynthesis of, 25 382 Cholinesterases, stracture of active surface, 10 130... 

Phenothiazines The phenothiazines (PTZs) undergo extensive metabolism. Metabolic routes include S-oxidation, aromatic hydroxylation, N-dealkylation, N-oxidation, and a combination of these processes. Chlorpromazine, for example, possesses 168 possible metabolites, a large proportion of which are pharmacologically active compounds. The development of an HPLC assay capable of resolving a large number of these metabolites is virtually impossible and assays that permit the simultaneous determination of the parent compound and a selected number of active metabolites must suffice. The PTZ group of compounds includes chlorpromazine, thioridazine, fluphenazine, and perphenazine. 

Chlorpromazine and other phenothiazines can be identified by their reactions with benzene-, toluene-o-, and toluene /j-stilbinic acids, and with p-hydroxy-, m-nitro-, w-amino-, and p-nitrobenzene stilbinic acids in an HCl medium. The reaction products are initially colorless masses but rapidly oxidize to yield colored products [32]. 

The oxidative titration of chlorpromazine with ceric sulfate or KBrOj-KBr in acid solution has been described, with the end point being determined by a dead-stop end point technique [55]. A similar method involving visual or potentiometric detection of the end point was also reported [56]. 

Chlorpromazine was quantitatively oxidized to either a free radical by 12N H2SO4, or to a sulfoxide by IN H2SO4 [148]. Electro-reduction of the free-radicals occurred at -0.25 V vs. S.C.E. on platinum wire. 

Chlorpromazine can be oxidized by aqueous bromine solutions, and after removal of any unconsumed bromine by sparging the solution with nitrogen, the sulfoxide oxidation product is determined by polarography... 

Takamura et al. have reported an electrochemical method for the determination of chlorpromazine with an anodically pretreated vitreous carbon electrode [164]. Optimal conditions for the pre-treatment were attained by the anodic oxidation of vitreous carbon electrodes in 0.5 mM phosphate buffer (pH 6.7) at 1.6 V V5. S.C.E. for 2 minutes. This was found to enhance the oxidation peak of the cyclic voltammogram for chlorpromazine by a factor of simeq 30. The peak current at +0.75 V was directly proportional to the concentration of chlorpromazine over the range of 0.2-40 pM and the detection limit was 0.1 pM. 

Ebel et al. have used a microliter vessel in the voltammetry and polarographic determination of small sample volumes of chlorpromazine [166]. The concentration of cells in glass or PTFE was described for use with a dropping-mercury electrode (sample volume 180 pL), a rotating disc electrode (sample volume 1 mL), or a stationary vitreous-carbon electrode (sample volume 80 pL). Chlorpromazine was determined using oxidative voltammetry at a 3 mm vitreous-carbon or a rotating electrode. 

Takamura et al. have reported a voltammetric method for the determination of chlorpromazine using an anodically oxidized carbon electrode [167]. A vitreous-carbon electrode was maintained at +1.6 V vi. S.C.E. for 2 minutes (in 0.5 M phosphate buffer at pH 6.8). Under these conditions, chlorpromazine gave an oxidation peak current on cyclic voltammograms that varied linearly with concentration over the range of 50 nM to 1 pM. 

Zimova et al. have determined chlorpromazine by differential pulse voltammetry in an acetonitrile medium [168]. The method involves oxidation of the derivative to the radical cation, with the reaction taking place in acetonitrile that is also 0.03M in perchloric acid. Maximum sensitivity was achieved with a scan rate of 2 mV/sec, a modulation amplitude of 50 mV, and a clock time of 40 seconds. 

Takamura et al. have determined chlorpromazine by the use of differential pulse voltammetry incorporating rotating glassy-carbon disc electrodes [170]. The determination was carried out after pre-treatment of vitreous carbon by anodic oxidation for two minutes in 0.5 M phosphate buffer (pH 6.3) at 1.6 V vs. Ag/AgCl reference electrode. The determination was made with the use of 50 mV pulses at 2 seconds intervals, a rotation rate of 2500 rpm, and a scan rate of 5 mV/sec. 

The electrochemical behavior of chlorpromazine hydrochloride in 0.2M H2SO4 was studied by cyclic and linear sweep voltammetry at an oxidized and a non-oxidized ruthenium wire electrode [173]. Preparation of a stable and permanent coating of RuOj on the electrode was very time-consuming, but the resulting curves were highly reproducible. The... 

White et al. have reported a rapid fluorimetric determination of chlorpromazine by an in situ photochemical oxidation [139]. Variable-angle synchronous scanning fluorescence spectroscopy has also been applied to the determination of chlorpromazine and its sulfoxide [140]. 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

Thio Ethers. Thio ethers are commonly oxidized to a sulfoxide or sulfone. The conversion of chlorpromazine to chlorpromazine sulfoxide is a good example of this. 

A typical example of the use of thin-layer coulometry to determine an n value is for the drug chlorpromazine (CPZ). A thin-layer coulogram for the oxidation of CPZ by a potential step to 575 mV vs. SCE is shown in Figure 3.13. A coulogram is also shown for the same potential step repeated in supporting electrolyte. 

Figure 3.13 Thin-layer controlled-potential coulometry of chlorpromazine (CPZ) oxidation in an optically transparent thin-layer cell. Ej = 250 mV Es = 575 mV Ef = 250 mV vs. SCE. 4.8 x 10-4 M CPZ, 3 M H2S04, and 3 M H2S04 alone. [From T. B. Jarbawi, Ph.D. dissertation, University of Cincinnati, 1981.]...

Tomiyasu, T., Sakamoto, H., and Yonehara, N., Catalytic determination of iron by a fixed-time method using the oxidation reaction of chlorpromazine with hydrogen peroxide, Analyt. Sci., 12, 507-509, 1996. 

Oxidation of promazine and chlorpromazine with hexaimidazolecobalt(III) in acidic solution results in the formation of Co(II) and a cationic radical. The kinetic and activation parameters have been determined and mechanistic aspects have been discussed.75... 

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