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Jacek Wojcikowski - One of the best experts on this subject based on the ideXlab platform.
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Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4
Pharmacological Reports, 2020Co-Authors: Przemysław J. Danek, Jacek Wojcikowski, Agnieszka Basińska-ziobroń, Wladyslawa A DanielAbstract:Background Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs. Methods The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3- N -demethylation (CYP1A1/2), diclofenac 4′-hydroxylation (CYP2C9), perazine N -demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Results The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. Conclusion Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.
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The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions
Pharmacological Reports, 2020Co-Authors: Przemysław J. Danek, Jacek Wojcikowski, Wladyslawa A DanielAbstract:Background The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). Methods The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3- N -demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N -demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism ( K _i = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism ( K _i = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 ( K _i = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism ( K _i = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 ( K _i = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 ( K _i = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism ( K _i = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism ( K _i = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity ( K _i = 37.5 and 85 µM in microsomes and supersomes). Conclusion The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.
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In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug–drug interactions
Pharmacological Reports, 2020Co-Authors: Jacek Wojcikowski, Przemysław J. Danek, Agnieszka Basińska-ziobroń, Renata Pukło, Wladyslawa A DanielAbstract:Background Inhibition of cytochrome P450 (CYP) enzymes is the most common cause of harmful drug–drug interactions. The present study aimed at examining the inhibitory effect of the novel antipsychotic drug asenapine on the main CYP enzymes in human liver. Methods The experiments were performed in vitro using pooled human liver microsomes and the human cDNA-expressed CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Supersomes). Activities of CYP enzymes were determined using the CYP-specific reactions: caffeine 3- N -demethylation (CYP1A2), diclofenac 4′-hydroxylation (CYP2C9), perazine N -demethylation (CYP2C19), bufuralol 1′-hydroxylation (CYP2D6), and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of asenapine using HPLC. Results The obtained results showed that both in human liver microsomes and Supersomes asenapine potently and to a similar degree inhibited the activity of CYP1A2 via a mixed mechanism ( K _ i = 3.2 μM in liver microsomes and Supersomes) and CYP2D6 via a competitive mechanism ( K _ i = 1.75 and 1.89 μM in microsomes and Supersomes, respectively). Moreover, asenapine attenuated the CYP3A4 activity via a non-competitive mechanism ( K _ i = 31.3 and 27.3 μM in microsomes and Supersomes, respectively). In contrast, asenapine did not affect the activity of CYP2C9 or CYP2C19. Conclusion The potent inhibition of CYP1A2 and CYP2D6 by asenapine, demonstrated in vitro, will most probably be observed also in vivo, since the calculated K _ i values are close to the presumed concentration range for asenapine in the liver in vivo. Therefore, pharmacokinetic interactions involving asenapine and CYP2D6 or CYP1A2 substrates are likely to occur during their co-administration to patients.
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inhibition of human cytochrome p450 isoenzymes by a phenothiazine neuroleptic levomepromazine an in vitro study
Pharmacological Reports, 2015Co-Authors: Agnieszka Basinskaziobron, Wladyslawa A Daniel, Jacek WojcikowskiAbstract:Abstract Background Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug–drug interactions. The present study was aimed at examining the inhibitory effect of the phenothiazine neuroleptic levomepromazine on main CYP isoenzymes in human liver. Methods The experiment was performed in vitro using the human cDNA-expressed CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Supersomes). CYP isoenzyme activities were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4′-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1′-hydroxylation (CYP2D6) and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of levomepromazine (1–50 μM). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by HPLC with UV or fluorimetric detection. Results Levomepromazine potently inhibited CYP2D6 ( K i = 6 μM) in a competitive manner. Moreover, the neuroleptic moderately diminished the activity of CYP1A2 ( K i = 47 μM) and CYP3A4 ( K i = 34 μM) via a mixed mechanism. On the other hand, levomepromazine did not affect the activities of CYP2C9 and CYP2C19. Conclusion The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K i values are below or close to the presumed concentration range for levomepromazine in the liver in vivo . Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs.
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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.
Wladyslawa A Daniel - One of the best experts on this subject based on the ideXlab platform.
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Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4
Pharmacological Reports, 2020Co-Authors: Przemysław J. Danek, Jacek Wojcikowski, Agnieszka Basińska-ziobroń, Wladyslawa A DanielAbstract:Background Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs. Methods The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3- N -demethylation (CYP1A1/2), diclofenac 4′-hydroxylation (CYP2C9), perazine N -demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Results The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. Conclusion Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.
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The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions
Pharmacological Reports, 2020Co-Authors: Przemysław J. Danek, Jacek Wojcikowski, Wladyslawa A DanielAbstract:Background The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). Methods The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3- N -demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N -demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism ( K _i = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism ( K _i = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 ( K _i = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism ( K _i = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 ( K _i = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 ( K _i = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism ( K _i = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism ( K _i = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity ( K _i = 37.5 and 85 µM in microsomes and supersomes). Conclusion The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.
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In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug–drug interactions
Pharmacological Reports, 2020Co-Authors: Jacek Wojcikowski, Przemysław J. Danek, Agnieszka Basińska-ziobroń, Renata Pukło, Wladyslawa A DanielAbstract:Background Inhibition of cytochrome P450 (CYP) enzymes is the most common cause of harmful drug–drug interactions. The present study aimed at examining the inhibitory effect of the novel antipsychotic drug asenapine on the main CYP enzymes in human liver. Methods The experiments were performed in vitro using pooled human liver microsomes and the human cDNA-expressed CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Supersomes). Activities of CYP enzymes were determined using the CYP-specific reactions: caffeine 3- N -demethylation (CYP1A2), diclofenac 4′-hydroxylation (CYP2C9), perazine N -demethylation (CYP2C19), bufuralol 1′-hydroxylation (CYP2D6), and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of asenapine using HPLC. Results The obtained results showed that both in human liver microsomes and Supersomes asenapine potently and to a similar degree inhibited the activity of CYP1A2 via a mixed mechanism ( K _ i = 3.2 μM in liver microsomes and Supersomes) and CYP2D6 via a competitive mechanism ( K _ i = 1.75 and 1.89 μM in microsomes and Supersomes, respectively). Moreover, asenapine attenuated the CYP3A4 activity via a non-competitive mechanism ( K _ i = 31.3 and 27.3 μM in microsomes and Supersomes, respectively). In contrast, asenapine did not affect the activity of CYP2C9 or CYP2C19. Conclusion The potent inhibition of CYP1A2 and CYP2D6 by asenapine, demonstrated in vitro, will most probably be observed also in vivo, since the calculated K _ i values are close to the presumed concentration range for asenapine in the liver in vivo. Therefore, pharmacokinetic interactions involving asenapine and CYP2D6 or CYP1A2 substrates are likely to occur during their co-administration to patients.
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inhibition of human cytochrome p450 isoenzymes by a phenothiazine neuroleptic levomepromazine an in vitro study
Pharmacological Reports, 2015Co-Authors: Agnieszka Basinskaziobron, Wladyslawa A Daniel, Jacek WojcikowskiAbstract:Abstract Background Inhibition of cytochrome P450 (CYP) isoenzymes is the most common cause of harmful drug–drug interactions. The present study was aimed at examining the inhibitory effect of the phenothiazine neuroleptic levomepromazine on main CYP isoenzymes in human liver. Methods The experiment was performed in vitro using the human cDNA-expressed CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 (Supersomes). CYP isoenzyme activities were determined using the CYP-specific reactions: caffeine 3-N-demethylation (CYP1A2), diclofenac 4′-hydroxylation (CYP2C9), perazine N-demethylation (CYP2C19), bufuralol 1′-hydroxylation (CYP2D6) and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of levomepromazine (1–50 μM). The concentrations of CYP-specific substrates and their metabolites formed by CYP isoenzymes were measured by HPLC with UV or fluorimetric detection. Results Levomepromazine potently inhibited CYP2D6 ( K i = 6 μM) in a competitive manner. Moreover, the neuroleptic moderately diminished the activity of CYP1A2 ( K i = 47 μM) and CYP3A4 ( K i = 34 μM) via a mixed mechanism. On the other hand, levomepromazine did not affect the activities of CYP2C9 and CYP2C19. Conclusion The inhibition of CYP1A2, CYP2D6 and CYP3A4 by levomepromazine, demonstrated in vitro in the present study, should also be observed in vivo (especially the CYP2D6 inhibition by levomepromazine), since the calculated K i values are below or close to the presumed concentration range for levomepromazine in the liver in vivo . Therefore pharmacokinetic interactions involving levomepromazine and CYP2D6, CYP1A2 or CYP3A4 substrates are likely to occur in patients during co-administration of the above-mentioned substrates/drugs.
Przemysław J. Danek - One of the best experts on this subject based on the ideXlab platform.
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Levomepromazine and clozapine induce the main human cytochrome P450 drug metabolizing enzyme CYP3A4
Pharmacological Reports, 2020Co-Authors: Przemysław J. Danek, Jacek Wojcikowski, Agnieszka Basińska-ziobroń, Wladyslawa A DanielAbstract:Background Cytochrome P450 (CYP) enzymes are involved in the metabolism of many important endogenous substrates (steroids, melatonin), drugs and toxic xenobiotics. Their induction accelerates drug metabolism and elimination. The present study aimed at examining the inducing abilities of two antipsychotic drugs levomepromazine and clozapine for the main CYPs. Methods The experiments were performed using cryopreserved human hepatocytes. The hepatotoxicity of levomepromazine and clozapine was assessed after exposure to the neuroleptics (LDH test). CYP activities were measured in the incubation medium using the CYP-specific reactions: caffeine 3- N -demethylation (CYP1A1/2), diclofenac 4′-hydroxylation (CYP2C9), perazine N -demethylation (CYP2C19) and testosterone 6β-hydroxylation (CYP3A4). In parallel, CYP mRNA levels were measured in neuroleptic-treated hepatocytes. Results The results indicate that levomepromazine and clozapine induce the expression of main CYP enzyme CYP3A4 in human hepatocytes. Levomepromazine and clozapine at concentrations of 2.5 and 10 µM, respectively, caused a significant increase in the mRNA level and activity of CYP3A4. Both neuroleptics did not produce any changes in CYP1A1/2, CYP2C9 and CYP2C19. Conclusion Levomepromazine and clozapine induce CYP3A4 in human hepatocytes in vitro. Further in vivo studies are advisable to confirm the CYP3A4 induction by levomepromazine and clozapine in the liver, and to assess the effect of these drugs on their own metabolism and on the biotransformation of other co-administered drugs which are the CYP3A4 substrates.
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The atypical neuroleptics iloperidone and lurasidone inhibit human cytochrome P450 enzymes in vitro. Evaluation of potential metabolic interactions
Pharmacological Reports, 2020Co-Authors: Przemysław J. Danek, Jacek Wojcikowski, Wladyslawa A DanielAbstract:Background The present study aimed at examining the inhibitory effect of two atypical neuroleptics iloperidone and lurasidone on the main human cytochrome P450 (CYP) enzymes in pooled human liver microsomes and cDNA-expressed CYP enzymes (supersomes). Methods The activity of these enzymes was determined by the following CYP-specific reactions: caffeine 3- N -demethylation/CYP1A2, diclofenac 4′-hydroxylation/CYP2C9, perazine N -demethylation/CYP2C19, bufuralol 1′-hydroxylation/CYP2D6 and testosterone 6β-hydroxylation/CYP3A4, respectively, using HPLC. Results Iloperidone inhibited the activity of CYP3A4 via a noncompetitive mechanism ( K _i = 0.38 and 0.3 µM in liver microsomes and supersomes, respectively) and CYP2D6 via a competitive mechanism ( K _i = 2.9 and 10 µM in microsomes and supersomes). Moreover, iloperidone attenuated the activity of CYP1A2 ( K _i = 45 and 31 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism ( K _i = 6.5 and 32 µM in microsomes and supersomes) but did not affect CYP2C9. Lurasidone moderately inhibited CYP1A2 ( K _i = 12.6 and 15.5 µM in microsomes and supersomes), CYP2C9 ( K _i = 18 and 3.5 µM in microsomes and supersomes) and CYP2C19 via a mixed mechanism ( K _i = 18 and 18.4 µM in microsomes and supersomes), and CYP3A4 via a competitive mechanism ( K _i = 29.4 and 9.1 µM in microsomes and supersomes). Moreover, lurasidone competitively, though weakly diminished the CYP2D6 activity ( K _i = 37.5 and 85 µM in microsomes and supersomes). Conclusion The examined neuroleptics showed inhibitory effects on different CYP enzymes. The obtained results indicate that metabolic/pharmacokinetic interactions with iloperidone (involving mainly CYP3A4 and CYP2D6) and possibly with lurasidone (involving CYP1A2, CYP2C9 or CYP2C19) may occur during combined therapy.
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In vitro inhibition of human cytochrome P450 enzymes by the novel atypical antipsychotic drug asenapine: a prediction of possible drug–drug interactions
Pharmacological Reports, 2020Co-Authors: Jacek Wojcikowski, Przemysław J. Danek, Agnieszka Basińska-ziobroń, Renata Pukło, Wladyslawa A DanielAbstract:Background Inhibition of cytochrome P450 (CYP) enzymes is the most common cause of harmful drug–drug interactions. The present study aimed at examining the inhibitory effect of the novel antipsychotic drug asenapine on the main CYP enzymes in human liver. Methods The experiments were performed in vitro using pooled human liver microsomes and the human cDNA-expressed CYP enzymes: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 (Supersomes). Activities of CYP enzymes were determined using the CYP-specific reactions: caffeine 3- N -demethylation (CYP1A2), diclofenac 4′-hydroxylation (CYP2C9), perazine N -demethylation (CYP2C19), bufuralol 1′-hydroxylation (CYP2D6), and testosterone 6β-hydroxylation (CYP3A4). The rates of the CYP-specific reactions were assessed in the absence and presence of asenapine using HPLC. Results The obtained results showed that both in human liver microsomes and Supersomes asenapine potently and to a similar degree inhibited the activity of CYP1A2 via a mixed mechanism ( K _ i = 3.2 μM in liver microsomes and Supersomes) and CYP2D6 via a competitive mechanism ( K _ i = 1.75 and 1.89 μM in microsomes and Supersomes, respectively). Moreover, asenapine attenuated the CYP3A4 activity via a non-competitive mechanism ( K _ i = 31.3 and 27.3 μM in microsomes and Supersomes, respectively). In contrast, asenapine did not affect the activity of CYP2C9 or CYP2C19. Conclusion The potent inhibition of CYP1A2 and CYP2D6 by asenapine, demonstrated in vitro, will most probably be observed also in vivo, since the calculated K _ i values are close to the presumed concentration range for asenapine in the liver in vivo. Therefore, pharmacokinetic interactions involving asenapine and CYP2D6 or CYP1A2 substrates are likely to occur during their co-administration to patients.
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.
Osamu Suzuki - One of the best experts on this subject based on the ideXlab platform.
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determination of phenothiazines in human body fluids by solid phase microextraction and liquid chromatography tandem mass spectrometry
Journal of Mass Spectrometry, 2000Co-Authors: Takeshi Kumazawa, Hiroshi Seno, Kanako Watanabesuzuki, Hideki Hattori, Akira Ishii, Keizo Sato, Osamu SuzukiAbstract:Eleven phenothiazine derivatives with heavy side-chains were found to be extractable from human whole blood and urine samples by solid-phase microextraction (SPME) with a polyacrylate-coated fiber. The fiber was then injected into the desorption chamber of an SPME–liquid chromatography (LC) interface for LC/tandem mass spectrometry (MS/MS) with positive ion electrospray (ES) ionization. All compounds formed base peaks due to [M + 1]+ ions by LC/ES-MS/MS. By use of LC/ES-MS/MS, the product ions produced from each [M + 1]+ ion showed base peaks due to side-chain liberation. Selected reaction monitoring (SRM) and selected ion monitoring (SIM) were compared for the detection of the 11 phenothiazine derivatives from human whole blood and urine. SRM showed much higher sensitivity than SIM for both types of sample. Therefore, a detailed procedure for the detection of drugs by SRM with SPME-LC/MS/MS was established and carefully validated. The extraction efficiencies of the 11 phenothiazine derivatives spiked into whole blood and urine were 0.0002–0.12 and 2.6–39.8%, respectively. The regression equations for the 11 phenothiazine derivatives showed excellent linearity with detection limits of 0.2–200 ng ml−1 for whole blood and 4–22 pg ml−1 for urine. The intra- and inter-day precisions for whole blood and urine samples were not greater than 15.1%. The data obtained after oral administration of perazine or flupentixol to a male subject are presented. Copyright © 2000 John Wiley & Sons, Ltd.