The Experts below are selected from a list of 168 Experts worldwide ranked by ideXlab platform
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.
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perazine at therapeutic drug concentrations inhibits human Cytochrome P450 Isoenzyme 1a2 cyp1a2 and caffeine metabolism an in vitro study
Pharmacological Reports, 2009Co-Authors: Jacek Wojcikowski, Wladyslawa A DanielAbstract:Abstract The aim of the present study was to estimate the inhibitory effect of perazine, a phenothiazine neuroleptic with piperazine structure in a side chain, on human CYP1A2 activity measured as a rate of caffeine 3-N- and 1-N-demethylation. Moreover, the influence of perazine on other caffeine metabolic pathways such as 7-N-demethylation (CYP1A2, CYP2C8/9, CYP3A4) and 8-hydroxylation (CYP3A4, CYP1A2, CYP2C8/9) was also determined. The Dixon analysis showed that in both human liver microsomes and Supersomes CYP1A2 perazine potently and to a similar degree inhibited caffeine 3-N-demethylation (K i = 3.5 μM) and 1-N-demethylation (K i = 5 μM). Perazine moderately diminished the rate of caffeine 7-N-demethylation in Supersomes CYP1A2 (K i = 11.5 μM) and liver microsomes (K i = 20 μM), and attenuated C-8-hydroxylation (K i = 15.5μM) in Supersomes CYP1A2. On the other hand, perazine weakly inhibited caffeine C-8-hydroxylation in liver microsomes (K i = 98 μM). About 80% of basal CYP1A2 activity was reduced by the therapeutic concentrations of perazine (5–10 μM). The obtained results show that perazine at its therapeutic concentrations is a potent inhibitor of human CYP1A2. Hence, taking account of CYP1A2 contribution to the metabolism of endogenous substances (steroids), drugs (xanthine derivatives, phenacetin, propranolol, imipramine, phenothiazine neuroleptics, clozapine) and carcinogenic compounds, the inhibition of CYP1A2 by perazine may be of physiological, pharmacological and toxicological importance.
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.
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metabolic mechanisms of caffeine catalyzed by Cytochrome P450 Isoenzyme 1a2 a theoretical study
Theoretical Chemistry Accounts, 2015Co-Authors: Zeqin Chen, Yuan Kang, Chenghua Zhang, Jing Tao, Ying XueAbstract:Caffeine (CA), a universally used psychoactive substance in foods and drugs, can cause osteoporosis when taken in moderate-to-high doses. The metabolic mechanisms of CA catalyzed by Cytochrome P450 Isoenzyme 1A2 (CYP1A2) were systematically explored in this study based on DFT calculation. Four possible metabolic pathways were investigated, namely 1-N, 3-N, 7-N demethylations, and C-8 hydroxylation. The results determined the mechanistic details and revealed some notable features. The rate-limiting C α –H hydroxylation for the N-demethylation mechanism proceeded predominantly through a hydrogen atom transfer mechanism with two-state reactivity. The generated carbinolamine decomposed in a non-enzymatic environment, especially through the adjacent heteroatom-assisted proton transfer. The rate-limiting step for C-8 hydroxylation involved the nucleophilic attack of the active Cpd I’s oxygen atom. Intriguingly, CA metabolic performance depended on the multiplicity of Cpd I. The 3-N demethylation metabolic mechanism predominated over the C-8 hydroxylation on the high-spin quartet state. Paraxanthine was the most energetically feasible metabolic product of CA. On the low-spin doublet state, however, C-8 hydroxylation had the lowest activation energy; hence, 1,3,7-trimethyluric acid was the optimum metabolic product of CA. All the results were in agreement with the experimental observation and can supply rational clues for the different metabolic performances of CA catalyzed by CYP1A2 in humans and rats. The calculated results in this study can provide more implications for the controversial amine N-dealkylation mechanisms by CYP and offer essential insights into bio-decaffeination techniques.
Mads Melbye - One of the best experts on this subject based on the ideXlab platform.
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concomitant use of statins and macrolide antibiotics and risk of serious renal events a nationwide cohort study
International Journal of Cardiology, 2018Co-Authors: Marie Lund, Henrik Svanstrom, Bjorn Pasternak, Anders Hviid, Mads MelbyeAbstract:Abstract Background Concomitant use of statins metabolized by the Cytochrome P450 Isoenzyme 3A4 (CYP3A4) and CYP3A4-inhibiting macrolide antibiotics may confer an increased risk of renal failure. We investigated the risk of serious renal events associated with concomitant use of such statins and such macrolides. Methods In a nationwide register-based cohort study (Denmark, 1999–2017), we identified 906,423 new users (40–79 years old), of CYP3A4-metabolized statins. In propensity score-matched analyses, we compared the risk of serious renal events during episodes of concomitant use of statins and CYP3A4-inhibiting macrolides (n = 71,521) with episodes of use of statins alone (n = 285,488) and, as the primary analysis, with episodes of concomitant use of statins and an active comparator (penicillin V, n = 139,446). Using proportional hazards regression, we estimated hazard ratios (HRs) for serious renal events within 30 days of start of follow-up. Results We observed 25 serious renal events during concomitant use of statins and macrolides (incidence rate [IR], 4.9 per 1000 person-years). Compared with use of statins alone (50 events; IR, 2.3), concomitant use of statins and macrolides was associated with a significantly increased risk of serious renal events (HR 2.16, 95% confidence interval [CI] 1.33, 3.49). Compared with concomitant use of statins and penicillin V (52 events; IR, 5.3), however, we observed no increased risk (HR 0.93, 95% CI 0.58, 1.49). Conclusions In this nationwide cohort study concomitant use of statins and macrolides was not associated with a significantly increased risk of serious renal events.
Jacek Wojcikowski - 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.
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perazine at therapeutic drug concentrations inhibits human Cytochrome P450 Isoenzyme 1a2 cyp1a2 and caffeine metabolism an in vitro study
Pharmacological Reports, 2009Co-Authors: Jacek Wojcikowski, Wladyslawa A DanielAbstract:Abstract The aim of the present study was to estimate the inhibitory effect of perazine, a phenothiazine neuroleptic with piperazine structure in a side chain, on human CYP1A2 activity measured as a rate of caffeine 3-N- and 1-N-demethylation. Moreover, the influence of perazine on other caffeine metabolic pathways such as 7-N-demethylation (CYP1A2, CYP2C8/9, CYP3A4) and 8-hydroxylation (CYP3A4, CYP1A2, CYP2C8/9) was also determined. The Dixon analysis showed that in both human liver microsomes and Supersomes CYP1A2 perazine potently and to a similar degree inhibited caffeine 3-N-demethylation (K i = 3.5 μM) and 1-N-demethylation (K i = 5 μM). Perazine moderately diminished the rate of caffeine 7-N-demethylation in Supersomes CYP1A2 (K i = 11.5 μM) and liver microsomes (K i = 20 μM), and attenuated C-8-hydroxylation (K i = 15.5μM) in Supersomes CYP1A2. On the other hand, perazine weakly inhibited caffeine C-8-hydroxylation in liver microsomes (K i = 98 μM). About 80% of basal CYP1A2 activity was reduced by the therapeutic concentrations of perazine (5–10 μM). The obtained results show that perazine at its therapeutic concentrations is a potent inhibitor of human CYP1A2. Hence, taking account of CYP1A2 contribution to the metabolism of endogenous substances (steroids), drugs (xanthine derivatives, phenacetin, propranolol, imipramine, phenothiazine neuroleptics, clozapine) and carcinogenic compounds, the inhibition of CYP1A2 by perazine may be of physiological, pharmacological and toxicological importance.
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.
