Chlorpromazine N-oxide

The first step of the photodegradation is the loss of an electron to yield the semiquinone free radical R. Further stages in the degradation yield the phenazathonium ion P, which is thought to react with water to yield chlorpromazine sulfoxide (CPO). The chlorpromazine sulfoxide is itself photolabile and further decomposition occurs. Other products of the photooxidation include chlorpromazine N-oxide and hydroxychlorpromazine. 

TJ Jaworski, EM Hawes, JW Hubbard, G McKay, KK Midha, The metabolites of chlorpromazine N-oxide in rat bile. Xenobiotica 21 1451, 1991. 

A Note on the Assay of Chlorpromazine N-Oxide and Its Sulfoxide in Plasma and Urine... 

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 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]. 

CPZ—Chlorpromazine PHTZ—Phenothiazine NO—N-Oxide SO—5-Oxide OH—3(7)-Hydroxy OG—0-Glucuronide OSOa"—Sulfate ester Nori—Monodesmethyl Nors—Didesmethyl... 

Sulfur is readily oxidized, nonenzymatically as well as enzymatically (Scheme 11.21). Chlorpromazine metabolism provides an example of S-oxidation by CYP3A (Scheme 11.22). Chlor promazine is also metabolized by N-oxidation and N-dealkylation pathways, resulting in a multiplicity of excreted products. 

Nicotine is an example of a compound that undergoes FM03-catalyzed N-oxidation, as shown in Scheme 11.27. About 4% of nicotine is stereoselec-tively metabolized to trans-(S)-(—)-nicotine N-V oxide in humans by FM03, whereas 30% of an administered dose appears as cotinine, a CYP2A6 product (34, 35). Other examples of FMO N-oxidation include trimethylamine, amphetamine, and the phenothi-azines (33). As described previously, FM03 catalyzes S-oxidation of substrates such as cimetidine, shown in Scheme 11.28, and chlorpromazine, also a CYP3A substrate (Scheme 11.22). 

Although it is difficult to predict which drugs are likely to be prone to photodegradation, there are certain chemical functions that are expected to introduce photoreactivity, including carbonyl, nitroaromatic and N-oxide functions, aryl halides, alkenes, polyenes and sulfides. The mechanisms of photodegradation are of such complexity as to have been fully elucidated in only a few cases. We will consider two examples - chlorpromazine and ketoprofen. 

Phase I reactions of chlorpromazine that have been reported include the following oxidative N-demethylation to yield the corresponding primary and secondary amines (368-371) aromatic hydroxylation to yield phenols (369-376) N -oxidation to yield the N-oxide (371, 372, 376, 377) S-oxidation to yield sulfoxide (369-373) and sulfone (378) oxidative deamination of the amino propyl side-chain (probably preceded by iV-demethyl-ation) to yield the carboxylic acid (371,379) ... 

PK Yeung, et al. Radioimmunoassay for the N-oxide metabolite of chlorpromazine in human plasma and its application to a pharmacokinetic study in healthy humans. J Pharm Sci 76 803, 1987. 

N-Oxidation, e.g. 2>acetylaminofluorene, nicotinamide trimethylamine, guanethidine, chlorpromazine, in pramine. 

In the presence of NADPH and oxygen, hepatic microsomal enzymes convert the following substrates to the corresponding N-oxides chlorpromazine, chlor-qrclizine. imipramine. nicotinamide, guanethidine, and trimethylamine. Based on limited data, it was sug sted that the formation of N-oxides might be an intermediate step in all microsomal N-dealkylations. It is now clear that although N-oxides are formed by liver microsomes, they are not obligatory intermediates in all N-dealky-lation reactions. 

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). 

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. 

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. 

Using 02 Anderson et al. showed that the two major phenolic metabolites of N-phenyl-2-naphthylamine produced by liver enzymes are likely to be derived via arene oxide intermediates. The mechanism by which bromo-benzene is converted to 4-bromocatechol in isolated rat hepatocytes was shown with 62 to proceed via dehydrogenation of a dihydrodiol intermediate rather than by two successive hydroxylation reactions of the substrate. Similar studies have been performed on chlorpromazine. 

Both investigations also reported the pulse radiolysis of solutes dissolved in ionic liquids. Behar et al. studied the effect of the presence of Oj and CCI4 in [bmim][PF6] their results suggested that the latter was a more effective radical scavenger. They also looked at the formation of the radical cations of chlorpromazine (ClPz-+) andN,N,7 r, N -tetramethyl-p-phenylenediamine (TPMD- ) in the same solvent. Finally, the kinetics of oxidation of ClPz in [bmim][PF( ] were studied. The experimentally determined bimolecular rate constant values were corrected for the high viscosity of the ionic liquid by estimation of the values of the diffusion-controlled rate constant, using Equation (5.3),... 

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