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Zhiyu Xue - One of the best experts on this subject based on the ideXlab platform.
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theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic Chlorpromazine catalyzed by cytochrome p450 isoenzyme 1a2
Theoretical Chemistry Accounts, 2016Co-Authors: Zeqin Chen, Yuan Kang, Jing Tao, Zhiyu Xue, Yan Zhang, Ying XueAbstract:Chlorpromazine, belonging to the first-generation antipsychotics, is known to cause some side effects, such as hepatotoxicity and agranulocytosis. The metabolic mechanisms of Chlorpromazine remain elusive up to now, but are thought to result in the formation of some reactive metabolites having side effects on the parent drug. The goal of this work was to explore the metabolic mechanisms of Chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2, a highly important activating enzyme of cytochrome P450 family, using DFT calculation. Three types of metabolic mechanisms were characterized, including S-oxidation, aromatic hydroxylation and N-dealkylation. The calculated results demonstrate that N 14-demethylation is the most thermodynamically and kinetically favorable metabolic pathway of Chlorpromazine, followed by S5-oxidation. Then, mono-N-desmethylChlorpromazine is the most feasible Chlorpromazine metabolite, which can occur further demethylation to form di-N-desmethylChlorpromazine. Besides, Chlorpromazine 5-sulfoxide and 7-hydroxyChlorpromazine are both the possible metabolites of Chlorpromazine. Interestingly, N-methyl hydroxylation, the rate-limiting step of N-demethylation, proceeds predominantly via a single-electron-transfer mechanism. All the proton transfer processes involved in the aromatic hydroxylation and N-dealkylation prefer to occurrence in a water-assisted enzymatic process. Each metabolic pathway proceeds in the spin-selective manner via the low-spin state of Cpd I. Our results are in good accordance with the experimental observations, which can provide some essential implications for the metabolic mechanisms of Chlorpromazine-like drugs.
Ying Xue - One of the best experts on this subject based on the ideXlab platform.
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theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic Chlorpromazine catalyzed by cytochrome p450 isoenzyme 1a2
Theoretical Chemistry Accounts, 2016Co-Authors: Zeqin Chen, Yuan Kang, Jing Tao, Zhiyu Xue, Yan Zhang, Ying XueAbstract:Chlorpromazine, belonging to the first-generation antipsychotics, is known to cause some side effects, such as hepatotoxicity and agranulocytosis. The metabolic mechanisms of Chlorpromazine remain elusive up to now, but are thought to result in the formation of some reactive metabolites having side effects on the parent drug. The goal of this work was to explore the metabolic mechanisms of Chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2, a highly important activating enzyme of cytochrome P450 family, using DFT calculation. Three types of metabolic mechanisms were characterized, including S-oxidation, aromatic hydroxylation and N-dealkylation. The calculated results demonstrate that N 14-demethylation is the most thermodynamically and kinetically favorable metabolic pathway of Chlorpromazine, followed by S5-oxidation. Then, mono-N-desmethylChlorpromazine is the most feasible Chlorpromazine metabolite, which can occur further demethylation to form di-N-desmethylChlorpromazine. Besides, Chlorpromazine 5-sulfoxide and 7-hydroxyChlorpromazine are both the possible metabolites of Chlorpromazine. Interestingly, N-methyl hydroxylation, the rate-limiting step of N-demethylation, proceeds predominantly via a single-electron-transfer mechanism. All the proton transfer processes involved in the aromatic hydroxylation and N-dealkylation prefer to occurrence in a water-assisted enzymatic process. Each metabolic pathway proceeds in the spin-selective manner via the low-spin state of Cpd I. Our results are in good accordance with the experimental observations, which can provide some essential implications for the metabolic mechanisms of Chlorpromazine-like drugs.
Wladyslawa A Daniel - One of the best experts on this subject based on the ideXlab platform.
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main contribution of the cytochrome p450 isoenzyme 1a2 cyp1a2 to n demethylation and 5 sulfoxidation of the phenothiazine neuroleptic Chlorpromazine in human liver a comparison with other phenothiazines
Biochemical Pharmacology, 2010Co-Authors: Jacek Wojcikowski, J Boksa, Wladyslawa A DanielAbstract:Abstract The aim of the present study was to identify cytochrome P450 (CYP) isoenzymes involved in the 5-sulfoxidation, mono-N-demethylation and di-N-demethylation of the aliphatic-type phenothiazine neuroleptic Chlorpromazine in human liver. Experiments were performed in vitro using cDNA-expressed human CYP isoforms (Supersomes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4), liver microsomes from different donors and CYP-selective inhibitors. The obtained results indicate that CYP1A2 is the only CYP isoform that catalyzes the mono-N-demethylation and di-N-demethylation of Chlorpromazine (100%) and is the main isoform responsible for Chlorpromazine 5-sulfoxidation (64%) at a therapeutic concentration of the drug (10 μM). CYP3A4 contributes to a lesser degree to Chlorpromazine 5-sulfoxidation (34%). The role of CYP2B6, CYP2C19 and CYP2D6 in catalyzing of the latter reaction is negligible (0.1–2%). Similar results were obtained at a higher, non-therapeutic concentration of the drug (100 μM); however, the contribution of CYP1A2 to Chlorpromazine mono-N-demethylation was noticeably lower (75%), mostly in favour of CYP2C19 and CYP3A4 (about 12% each). The obtained results indicate that the catalysis of Chlorpromazine N-demethylation and 5-sulfoxidation in humans exhibits a stricter CYP1A2 preference compared to the previously tested phenothiazines (promazine, perazine, and thioridazine). Hence pharmacokinetic interactions involving Chlorpromazine and CYP1A2 substrates and inhibitors are likely to occur. Considering strong dopaminergic D2, noradrenergic α1 and cholinergic M1 receptor blocking properties of Chlorpromazine and some of its metabolites, as well as their serious side effects, the obtained results may be of pharmacological and clinical importance.
Yan Zhang - One of the best experts on this subject based on the ideXlab platform.
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theoretical elucidation of the metabolic mechanisms of phenothiazine neuroleptic Chlorpromazine catalyzed by cytochrome p450 isoenzyme 1a2
Theoretical Chemistry Accounts, 2016Co-Authors: Zeqin Chen, Yuan Kang, Jing Tao, Zhiyu Xue, Yan Zhang, Ying XueAbstract:Chlorpromazine, belonging to the first-generation antipsychotics, is known to cause some side effects, such as hepatotoxicity and agranulocytosis. The metabolic mechanisms of Chlorpromazine remain elusive up to now, but are thought to result in the formation of some reactive metabolites having side effects on the parent drug. The goal of this work was to explore the metabolic mechanisms of Chlorpromazine catalyzed by cytochrome P450 isoenzyme 1A2, a highly important activating enzyme of cytochrome P450 family, using DFT calculation. Three types of metabolic mechanisms were characterized, including S-oxidation, aromatic hydroxylation and N-dealkylation. The calculated results demonstrate that N 14-demethylation is the most thermodynamically and kinetically favorable metabolic pathway of Chlorpromazine, followed by S5-oxidation. Then, mono-N-desmethylChlorpromazine is the most feasible Chlorpromazine metabolite, which can occur further demethylation to form di-N-desmethylChlorpromazine. Besides, Chlorpromazine 5-sulfoxide and 7-hydroxyChlorpromazine are both the possible metabolites of Chlorpromazine. Interestingly, N-methyl hydroxylation, the rate-limiting step of N-demethylation, proceeds predominantly via a single-electron-transfer mechanism. All the proton transfer processes involved in the aromatic hydroxylation and N-dealkylation prefer to occurrence in a water-assisted enzymatic process. Each metabolic pathway proceeds in the spin-selective manner via the low-spin state of Cpd I. Our results are in good accordance with the experimental observations, which can provide some essential implications for the metabolic mechanisms of Chlorpromazine-like drugs.
Yinhuan Li - One of the best experts on this subject based on the ideXlab platform.
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sensitive determination of phenothiazines in pharmaceutical preparation and biological fluid by flow injection chemiluminescence method using luminol kmno4 system
Talanta, 2007Co-Authors: Jiuru Lu, Yinhuan LiAbstract:Abstract A flow injection chemiluminescence method was described for the determination of four phenothiazine drugs, namely, Chlorpromazine hydrochloride, perphenazine hydrochloride, fluphenazine hydrochloride and thioridazine hydrochloride. Strong Chemiluminescence (CL) signal was produced when above-mentioned drug was injected into the mixed stream of luminol with KMnO4. The linear ranges of the method were 0.0020–1.0 μg/mL Chlorpromazine hydrochloride, 0.0040–3.0 μg/mL perphenazine hydrochloride, 0.0020–5.0 μg/mL fluphenazine hydrochloride and 0.0050–1.0 μg/mL thioridazine hydrochloride. The detection limits were 0.4 ng/mL Chlorpromazine hydrochloride, 0.7 ng/mL perphenazine hydrochloride, 2 ng/mL fluphenazine hydrochloride and 0.7 ng/mL thioridazine hydrochloride. The proposed method was applied to the determination of Chlorpromazine hydrochloride in injections and in mental patient's urine samples and the satisfactory results were achieved. The possible CL reaction mechanism was also discussed briefly.