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Jeremy K Nicholson - One of the best experts on this subject based on the ideXlab platform.
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directly coupled hplc nmr spectroscopic studies of metabolism and futile deacetylation of Phenacetin in the rat
Journal of Pharmaceutical and Biomedical Analysis, 1999Co-Authors: A W Nicholls, John C Lindon, Ian D Wilson, Duncan R Farrant, John P Shockcor, Jeremy K NicholsonAbstract:Abstract The metabolism and futile deacetylation of Phenacetin has been investigated in the rat via 1 H NMR spectroscopic analysis of urine. Animals were dosed with either Phenacetin or Phenacetin–C 2 H 3 and urine samples were collected for −24–0 (pre-dosing), 0–8, 8–24, and 24–48 h post-dosing. Drug metabolites of the two compounds were concentrated from the urine using solid-phase extraction prior to the use of directly-coupled HPLC- 1 H NMR spectroscopy for separation and identification. Following dosing of Phenacetin, the metabolites identified were paracetamol glucuronide, paracetamol and N -hydroxyparacetamol, whilst paracetamol and N -hydroxyparacetamol sulphate were identified following dosing of Phenacetin–C 2 H 3 . Quantitatively the percentage futile deacetylation of Phenacetin–C 2 H 3 metabolites was found to be 32% in both paracetamol and N -hydroxyparacetamol sulphate. This study further indicated the importance of futile deacetylation in simple analgesics and the value of directly-coupled HPLC-NMR spectroscopy for the study of this process.
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nmr spectroscopic studies on the metabolism and futile deacetylation of Phenacetin in the rat
Xenobiotica, 1997Co-Authors: A W Nicholls, John C Lindon, Stephen Caddick, R D Farrant, Ian D Wilson, Jeremy K NicholsonAbstract:1. 1H-NMR spectroscopy of urine was used to determine the % deacetylation and re-acetylation of 2H-labelled (in the acetyl) Phenacetin metabolites in the rat. 2. Male Sprague- Dawley rats were each dosed with either Phenacetin or Phenacetin C2H8 at 50 mg kg−1. The total urinary recoveries for Phenacetin and Phenacetin-C2H8 were 47.6 ± 16.7 and 50.1 ± 16.2% respectively (not significantly different, p > 0.05). Paracetamol sulphate and glucuronide are the major urinary metabolites of both protio and deuteriophenace tin. 3. The futile deacetylationgiven by the urinary recovery of protio-acetyl metabolitesof Phenacetin-C2H8 was 29.6 ± 0.9% for paracetamol sulphate and 36.6 ± 3.1% for paracetamol glucuronide. These observations demonstrate a high level of futile deacetylation in the paracetamol conjugates formed by metabolism of Phenacetin-C2H8 and this may indicate a high metabolic flux through the nephrotoxic intermediate 4-aminophenol. 4. The level of futile deacetylation for Phenacetin was significantly hi...
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application of capillary electrophoresis mass spectrometry to the analysis of urine samples from animals and man containing paracetamol and Phenacetin and their metabolites
Analytical Communications, 1997Co-Authors: Alison E Ashcroft, Ian D Wilson, Hilary Major, Andy Nicholls, Jeremy K NicholsonAbstract:Capillary electrophoresis, in combination with electrospray mass spectrometry (CE–ESMS), has been applied to the analysis of Phenacetin and paracetamol and its metabolites in freeze dried urine, and solid phase extracts of urine, following administration to rat and man. Using CE–ESMS the detection of 2 pg of d 3 -paracetamol on column was possible. Phenacetin, paracetamol and paracetamol glucuronide and sulfate were all readily detectable in the samples. The CE–ESMS method was also used to determine the extent of deacetylation/reacetylation of d 3 -acetyl-labelled paracetamol in vivo.
Tsuyoshi Yokoi - One of the best experts on this subject based on the ideXlab platform.
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metabolic activation by human arylacetamide deacetylase cyp2e1 and cyp1a2 causes Phenacetin induced methemoglobinemia
Biochemical Pharmacology, 2012Co-Authors: Yuki Kobayashi, Tatsuki Fukami, Miki Nakajima, Ryota Higuchi, Tsuyoshi YokoiAbstract:Phenacetin has been used as an analgesic antipyretic but has now been withdrawn from the market due to adverse effects such as methemoglobinemia and renal failure. It has been suggested that metabolic activation causes these adverse effects; yet, the precise mechanisms remain unknown. We previously demonstrated that human arylacetamide deacetylase (AADAC) was the principal enzyme catalyzing the hydrolysis of Phenacetin. In this study, we assessed whether AADAC was involved in Phenacetin-induced methemoglobinemia. A high methemoglobin (Met-Hb) level in the blood was detected 1 h after administration of Phenacetin (250 mg/kg, p.o.) to male C57BL/6 mice. Pre-administration of tri-o-tolylphosphate, a general esterase inhibitor, was found to decrease the levels of Met-Hb and the plasma concentration of p-phenetidine, a hydrolyzed metabolite of Phenacetin. An in vitro study using red blood cells revealed that incubation of Phenacetin or p-phenetidine with human liver microsomes (HLM) increased the formation of Met-Hb. To identify the enzymes involved in the formation of Met-Hb, we used recombinant enzymes and HLM treated with inhibitors in the measurement of the formation of Met-Hb. High levels of Met-Hb were observed following incubation of human AADAC with either cytochrome P450 (CYP) 1A2 or CYP2E1. Furthermore, the increased Met-Hb formation by the incubation of HLM with Phenacetin was significantly inhibited to 25.1 ± 0.7% of control by eserine, a potent AADAC inhibitor. In conclusion, we found that the hydrolysis by AADAC and subsequent metabolism by CYP1A2 and CYP2E1 play predominant roles in Phenacetin-induced methemoglobinemia.
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arylacetamide deacetylase is a determinant enzyme for the difference in hydrolase activities of Phenacetin and acetaminophen
Drug Metabolism and Disposition, 2010Co-Authors: Akinobu Watanabe, Tatsuki Fukami, Shiori Takahashi, Yuki Kobayashi, Nao Nakagawa, Miki Nakajima, Tsuyoshi YokoiAbstract:Phenacetin was withdrawn from the market because it caused renal failure in some patients. Many reports indicated that the nephrotoxicity of Phenacetin is associated with the hydrolyzed metabolite, p-phenetidine. Acetaminophen (APAP), the major metabolite of Phenacetin, is also hydrolyzed to p-aminophenol, which is a nephrotoxicant. However, APAP is safely prescribed if used in normal therapeutic doses. This background prompted us to investigate the difference between Phenacetin and APAP hydrolase activities in human liver. In this study, we found that Phenacetin is efficiently hydrolyzed in human liver microsomes (HLM) [CL(int) 1.08 +/- 0.02 microl/(min . mg)], whereas APAP is hardly hydrolyzed [0.02 +/- 0.00 microl/(min . mg)]. To identify the esterase involved in their hydrolysis, the activities were measured using recombinant human carboxylesterase (CES) 1A1, CES2, and arylacetamide deacetylase (AADAC). Among these, AADAC showed a K(m) value (1.82 +/- 0.02 mM) similar to that of HLM (3.30 +/- 0.16 mM) and the highest activity [V(max) 6.03 +/- 0.14 nmol/(min . mg)]. In contrast, APAP was poorly hydrolyzed by the three esterases. The large contribution of AADAC to Phenacetin hydrolysis was demonstrated by the prediction with a relative activity factor. In addition, the Phenacetin hydrolase activity by AADAC was activated by flutamide (5-fold) as well as that in HLM (4-fold), and the activity in HLM was potently inhibited by eserine, a strong inhibitor of AADAC. In conclusion, we found that AADAC is the principal enzyme responsible for the Phenacetin hydrolysis, and the difference of hydrolase activity between Phenacetin and APAP is largely due to the substrate specificity of AADAC.
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activation of Phenacetin o deethylase activity by α naphthoflavone in human liver microsomes
Xenobiotica, 1999Co-Authors: Miki Nakajima, K Kobayashi, K Oshima, N Shimada, S Tokudome, K Chiba, Tsuyoshi YokoiAbstract:1. The roles of different human cytochrome P450s (CYP) in Phenacetin O-deethylation were investigated using human liver microsomes and recombinant proteins. Phenacetin O-deethylase (POD) activities in human liver microsomes at substrate concentrations of 10 and 500 μM were inhibited by 0.1 and 1 μM α-naphthoflavone and activated by 10 and 100 μM α-naphthoflavone. The activation of POD activity in human liver microsomes by α-naphthoflavone was inhibited by 100 μM aniline, anti-CYP2E1 antibody, 1 μM ketoconazole and anti-CYP3A4 antibody. 2. In recombinant CYP from human B-lymphoblast cells, POD activities at a Phenacetin concentration of 500 μM were detected for CYP2E1 and CYP3A4, as well as CYP1A2, CYP1A1, CYP2C19, CYP2C9 and CYP2A6. In recombinant CYP from human B-lymphoblast cells or baculovirus-infected insect cells and in reconstituted systems, a requirement of cytochrome b5 (b5) for POD activities catalysed by CYP2E1 and CYP3A4 was observed. The activation of POD activity by α-naphthoflavone was obser...
Emilio Perucca - One of the best experts on this subject based on the ideXlab platform.
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effect of active and passive cigarette smoking on cyp1a2 mediated Phenacetin disposition in chinese subjects
Therapeutic Drug Monitoring, 1998Co-Authors: Xiao S Dong, A Bartoli, G Gatti, Zhi Z Ping, Zhong W Xiao, Chong C Shu, S Durso, Emilio PeruccaAbstract:The effect of active and passive cigarette smoking on CYP1A2-mediated Phenacetin disposition was evaluated in a controlled study of 36 healthy Chinese subjects. Each subject was administered a single oral dose of Phenacetin (900 mg), and frequent blood samples were taken for up to 12 hours for simultaneous high-pressure liquid chromatography determinations of plasma concentrations of Phenacetin and metabolically derived paracetamol. Compared with values observed in controls not exposed to cigarette smoking, subjects who smoked 7 to 40 (median, 20) cigarettes per day exhibited a 2.5-fold higher Phenacetin apparent oral clearance (7.2, 4.3-12.0 L x h(-1) x kg(-1) vs 2.9, 1.8-4.6 L x h(-1) x kg(-1) [geometric means, 95% confidence intervals]; n = 12, p < 0.05). In subjects exposed to passive smoking, Phenacetin's apparent oral clearance (3.6, 2.0-46.6 L x h(-1) x kg(-1), n = 12) was intermediate between the values observed in the two other groups. Plasma paracetamol levels were moderately lower in active smokers than in passive smokers and controls. These results demonstrated that, in contrast to results found in previous studies, Chinese subjects were fully susceptible to the inducing effect of cigarette smoke on CYP1A2 activity.
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the influence of ethnic factors and gender on cyp1a2 mediated drug disposition a comparative study in caucasian and chinese subjects using Phenacetin as a marker substrate
Therapeutic Drug Monitoring, 1996Co-Authors: A Bartoli, S Xiaodong, G Gatti, G Cipolla, Roberto Marchiselli, Emilio PeruccaAbstract:To assess potential ethnic and gender-related differences in the expression of cytochrome CYP1A2-mediated activity, the pharmacokinetics of Phenacetin (a CYP1A2 substrate) and its metabolite paracetamol were compared in 20 Caucasian and 20 Chinese subjects after administration of a single oral 900 mg Phenacetin dose. Peak plasma concentrations and apparent oral clearance values for Phenacetin did not differ between the two groups (geometric means: 3.4 micrograms/ml and 1.56 ml h-1 kg-1, respectively, for Caucasians vs. 4.7 micrograms/ml and 1.25 ml h-1 kg-1, respectively, for Chinese, after excluding one Caucasian with aberrantly low plasma Phenacetin values). Pharmacokinetic parameters for metabolically derived paracetamol were also similar in the two groups. When subjects were divided into subgroups according to gender, Phenacetin apparent oral clearance values were found to be lower in Chinese women compared with both Chinese men and Caucasian subjects of either sex. It is concluded that there are no major interethnic differences in the expression of CYP1A2-related activity between Caucasians and Chinese, although Chinese women as a subgroup may exhibit comparatively lower enzyme activity.
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omeprazole does not enhance the metabolism of Phenacetin a marker of cyp1a2 activity in healthy volunteers
Therapeutic Drug Monitoring, 1994Co-Authors: S Xiaodong, A Bartoli, G Gatti, G Cipolla, F Crema, Emilio PeruccaAbstract:Omeprazole has been reported to increase cytochrome P450IA2 (CYP1A2) activity in vitro, but whether this effect also occurs in vivo is controversial. To clarify this issue, the effect of omeprazole (20 mg/day for 8 days) on the kinetics and metabolism of Phenacetin, an in vivo marker of CYP1A2 activity, was examined in 10 healthy volunteers. The pharmacokinetic parameters of Phenacetin and metabolically derived paracetamol on the 8th day of omeprazole administration were very similar to those observed in a control session in the absence of omeprazole administration, the only significant difference being a higher peak plasma Phenacetin concentration during omeprazole treatment. It is concluded that at the dosage used omeprazole does not increase the rate of oxidative and conjugative reactions involved in the metabolism of Phenacetin and paracetamol respectively. These data are consistent with the hypothesis that omeprazole is generally devoid of inducing effects on CYP1A2 activity in vivo, at least in a Caucasian population with a low prevalence of the omeprazole-mephenytoin poor metabolizer phenotype.
Patrick Jame - One of the best experts on this subject based on the ideXlab platform.
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irms to study a common cocaine cutting agent Phenacetin
Drug Testing and Analysis, 2017Co-Authors: Virginie Ladroue, Laurence Dujourdy, Fabrice Besacier, Patrick JameAbstract:Phenacetin is a pharmaceutical closely related to acetaminophen that has been banned in France for a long time due to its nephritic and carcinogenic adverse effects. It frequently appears in cocaine seizures as a cutting agent. Following both sanitary and intelligence motivations, this molecule was chosen for this study, and stable isotopes seemed to be the most appropriate tool. A total of 228 seized samples were collected over a 6-year period, and 8 standards of known origin were purchased. They were submitted to gas chromatography (GC) or elemental analysis - isotope ratio mass spectrometry (EA-IRMS) measurements, depending on their complexity. Stable isotope ratios of carbon, hydrogen, and nitrogen for a part of the sample set, were acquired. The isotopic values of Phenacetin standards acquired from various providers located worldwide are quite spread, which indicates that stable isotopes could be used to discriminate manufacturers. However, the measured values of most of the seized samples are concentrated in a narrow range, tending to demonstrate that Phenacetin is smuggled from a single source or similar ones. Consequently, stable isotopes could only be used to exclude that several samples come from a common source. Copyright © 2016 John Wiley & Sons, Ltd.
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irms to study a common cocaine cutting agent Phenacetin
Drug Testing and Analysis, 2017Co-Authors: Virginie Ladroue, Laurence Dujourdy, Fabrice Besacier, Patrick JameAbstract:Phenacetin is a pharmaceutical closely related to acetaminophen that has been banned in France for a long time due to its nephritic and carcinogenic adverse effects. It frequently appears in cocaine seizures as a cutting agent. Following both sanitary and intelligence motivations, this molecule was chosen for this study, and stable isotopes seemed to be the most appropriate tool. A total of 228 seized samples were collected over a 6-year period, and 8 standards of known origin were purchased. They were submitted to gas chromatography (GC) or elemental analysis - isotope ratio mass spectrometry (EA-IRMS) measurements, depending on their complexity. Stable isotope ratios of carbon, hydrogen, and nitrogen for a part of the sample set, were acquired. The isotopic values of Phenacetin standards acquired from various providers located worldwide are quite spread, which indicates that stable isotopes could be used to discriminate manufacturers. However, the measured values of most of the seized samples are concentrated in a narrow range, tending to demonstrate that Phenacetin is smuggled from a single source or similar ones. Consequently, stable isotopes could only be used to exclude that several samples come from a common source. Copyright © 2016 John Wiley & Sons, Ltd.
A W Nicholls - One of the best experts on this subject based on the ideXlab platform.
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directly coupled hplc nmr spectroscopic studies of metabolism and futile deacetylation of Phenacetin in the rat
Journal of Pharmaceutical and Biomedical Analysis, 1999Co-Authors: A W Nicholls, John C Lindon, Ian D Wilson, Duncan R Farrant, John P Shockcor, Jeremy K NicholsonAbstract:Abstract The metabolism and futile deacetylation of Phenacetin has been investigated in the rat via 1 H NMR spectroscopic analysis of urine. Animals were dosed with either Phenacetin or Phenacetin–C 2 H 3 and urine samples were collected for −24–0 (pre-dosing), 0–8, 8–24, and 24–48 h post-dosing. Drug metabolites of the two compounds were concentrated from the urine using solid-phase extraction prior to the use of directly-coupled HPLC- 1 H NMR spectroscopy for separation and identification. Following dosing of Phenacetin, the metabolites identified were paracetamol glucuronide, paracetamol and N -hydroxyparacetamol, whilst paracetamol and N -hydroxyparacetamol sulphate were identified following dosing of Phenacetin–C 2 H 3 . Quantitatively the percentage futile deacetylation of Phenacetin–C 2 H 3 metabolites was found to be 32% in both paracetamol and N -hydroxyparacetamol sulphate. This study further indicated the importance of futile deacetylation in simple analgesics and the value of directly-coupled HPLC-NMR spectroscopy for the study of this process.
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nmr spectroscopic studies on the metabolism and futile deacetylation of Phenacetin in the rat
Xenobiotica, 1997Co-Authors: A W Nicholls, John C Lindon, Stephen Caddick, R D Farrant, Ian D Wilson, Jeremy K NicholsonAbstract:1. 1H-NMR spectroscopy of urine was used to determine the % deacetylation and re-acetylation of 2H-labelled (in the acetyl) Phenacetin metabolites in the rat. 2. Male Sprague- Dawley rats were each dosed with either Phenacetin or Phenacetin C2H8 at 50 mg kg−1. The total urinary recoveries for Phenacetin and Phenacetin-C2H8 were 47.6 ± 16.7 and 50.1 ± 16.2% respectively (not significantly different, p > 0.05). Paracetamol sulphate and glucuronide are the major urinary metabolites of both protio and deuteriophenace tin. 3. The futile deacetylationgiven by the urinary recovery of protio-acetyl metabolitesof Phenacetin-C2H8 was 29.6 ± 0.9% for paracetamol sulphate and 36.6 ± 3.1% for paracetamol glucuronide. These observations demonstrate a high level of futile deacetylation in the paracetamol conjugates formed by metabolism of Phenacetin-C2H8 and this may indicate a high metabolic flux through the nephrotoxic intermediate 4-aminophenol. 4. The level of futile deacetylation for Phenacetin was significantly hi...