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James A. Ruth - One of the best experts on this subject based on the ideXlab platform.
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Fentanyl in Hair
Drug Metabolism and Disposition, 1998Co-Authors: Peter R. Stout, Douglas J Claffey, James A. RuthAbstract:The levels of fentanyl extractable from mouse hair after chronic systemic administration and the suitability of externally loaded hair samples for establishing control and comparison samples were determined. Additionally, the effects of chemical modification of specific polar functionalities within the hair protein matrix on the deposition and recovery of fentanyl in hair subjected to external loading were determined. BALB/c mice entering a second phase of synchronized hair growth were treated ip with fentanyl (0.02, 0.05, or 0.10 mg/kg) on Monday, Wednesday, and Friday for 3 weeks. At that time, fentanyl concentrations in hair, as determined by GC/MS, were 0.025–0.050 ng/mg of hair. Hair samples exposed to fentanyl in phosphate buffer (ionized Drug) showed no significant accumulation of Drug into the hair, as determined by loss of fentanyl from the loading solution or by extraction of the hair. Hair samples exposed to nonionized fentanyl in methanolic solution (10, 50, and 100 ng/ml) showed significant accumulation of Drug in the hair and significant removal of Drug from the incubation solution. Fentanyl removal from solution plateaued after 24 hr, suggesting equilibration between fentanyl in solution and fentanyl in the hair. A mass balance between Drug lost from the incubation solution and Drug recovered from hair samples suggests that 94% of accumulated fentanyl is tightly bound to the hair matrix or resides in water-inaccessible compartments within the hair. These results suggest that fentanyl accumulation after in vivo administration differs, in the nature of storage, from fentanyl accumulation from external solutions and that external spiking of hair may not provide suitable control samples. Chemical modification of hair protein functionalities (reaction with diazomethane to esterify carboxylic acid groups or with acetic anhydride and pyridine to acetylate amine and hydroxyl functionalities) led to reproducible protein structure modification, as demonstrated by Fourier transform-IR and by pH titration. Hair from BALB/c mice was used. The accumulation of fentanyl was examined in hair samples exposed to fentanyl in methanol or methylene chloride solutions (10 ng/ml, 24 hr). Fentanyl was recovered from hair by 24-hr extraction in phosphate buffer, pH 6. Esterification of hair resulted in significantly less uptake of nonionized fentanyl from a methanolic solution and significantly lower recovery of Drug from hair, relative to untreated hair, suggesting that carboxylic acid functionalities are necessary for the incorporation of Drug. Acetylation of hair resulted in increased removal of fentanyl from methylene chloride solutions and increased recovery of fentanyl. This is consistent with the creation or expansion of a less polar compartment. Fentanyl uptake from a methanolic solution was also greater in acetylated hair. These results demonstrate that solution-accessible ionizable functionalities of hair play a significant role in the accumulation and retention of nonionized fentanyl from organic solutions.
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Chemical factors involved in accumulation and retention of fentanyl in hair after external exposure or in vivo deposition
Drug Metabolism and Disposition, 1998Co-Authors: Peter R. Stout, Douglas J Claffey, James A. RuthAbstract:The levels of fentanyl extractable from mouse hair after chronic systemic administration and the suitability of externally loaded hair samples for establishing control and comparison samples were determined. Additionally, the effects of chemical modification of specific polar functionalities within the hair protein matrix on the deposition and recovery of fentanyl in hair subjected to external loading were determined. BALB/c mice entering a second phase of synchronized hair growth were treated ip with fentanyl (0.02, 0.05, or 0.10 mg/kg) on Monday, Wednesday, and Friday for 3 weeks. At that time, fentanyl concentrations in hair, as determined by GC/ MS, were 0.025-0.050 ng/mg of hair. Hair samples exposed to fentanyl in phosphate buffer (ionized Drug) showed no significant accumulation of Drug into the hair, as determined by loss of fentanyl from the loading solution or by extraction of the hair. Hair samples exposed to nonionized fentanyl in methanolic solution (10, 50, and 100 ng/ml) showed significant accumulation of Drug in the hair and significant removal of Drug from the incubation solution. Fentanyl removal from solution plateaued after 24 hr, suggesting equilibration between fentanyl in solution and fentanyl in the hair. A mass balance between Drug lost from the incubation solution and Drug recovered from hair samples suggests that 94% of accumulated fentanyl is tightly bound to the hair matrix or resides in water-inaccessible compartments within the hair. These results suggest that fentanyl accumulation after in vivo administration differs, in the nature of storage, from fentanyl accumulation from external solutions and that external spiking of hair may not provide suitable control samples. Chemical modification of hair protein functionalities (reaction with diazomethane to esterify carboxylic acid groups or with acetic anhydride and pyridine to acetylate amine and hydroxyl functionalities) led to reproducible protein structure modification, as demonstrated by Fourier transform-IR and by pH titration. Hair from BALB/c mice was used. The accumulation of fentanyl was examined in hair samples exposed to fentanyl in methanol or methylene chloride solutions (10 ng/ml, 24 hr). Fentanyl was recovered from hair by 24-hr extraction in phosphate buffer, pH 6. Esterification of hair resulted in significantly less uptake of nonionized fentanyl from a methanolic solution and significantly lower recovery of Drug from hair, relative to untreated hair, suggesting that carboxylic acid functionalities are necessary for the incorporation of Drug. Acetylation of hair resulted in increased removal of fentanyl from methylene chloride solutions and increased recovery of fentanyl. This is consistent with the creation or expansion of a less polar compartment. Fentanyl uptake from a methanolic solution was also greater in acetylated hair. These results demonstrate that solution-accessible ionizable functionalities of hair play a significant role in the accumulation and retention of nonionized fentanyl from organic solutions.
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Fentanyl in hair - Chemical factors involved in accumulation and retention of fentanyl in hair after external exposure or in vivo deposition
Drug metabolism and disposition: the biological fate of chemicals, 1998Co-Authors: Peter R. Stout, Douglas J Claffey, James A. RuthAbstract:The levels of fentanyl extractable from mouse hair after chronic systemic administration and the suitability of externally loaded hair samples for establishing control and comparison samples were determined. Additionally, the effects of chemical modification of specific polar functionalities within the hair protein matrix on the deposition and recovery of fentanyl in hair subjected to external loading were determined. BALB/c mice entering a second phase of synchronized hair growth were treated ip with fentanyl (0.02, 0.05, or 0.10 mg/kg) on Monday, Wednesday, and Friday for 3 weeks. At that time, fentanyl concentrations in hair, as determined by GC/MS, were 0.025–0.050 ng/mg of hair. Hair samples exposed to fentanyl in phosphate buffer (ionized Drug) showed no significant accumulation of Drug into the hair, as determined by loss of fentanyl from the loading solution or by extraction of the hair. Hair samples exposed to nonionized fentanyl in methanolic solution (10, 50, and 100 ng/ml) showed significant accumulation of Drug in the hair and significant removal of Drug from the incubation solution. Fentanyl removal from solution plateaued after 24 hr, suggesting equilibration between fentanyl in solution and fentanyl in the hair. A mass balance between Drug lost from the incubation solution and Drug recovered from hair samples suggests that 94% of accumulated fentanyl is tightly bound to the hair matrix or resides in water-inaccessible compartments within the hair. These results suggest that fentanyl accumulation afterin vivo administration differs, in the nature of storage, from fentanyl accumulation from external solutions and that external spiking of hair may not provide suitable control samples. Chemical modification of hair protein functionalities (reaction with diazomethane to esterify carboxylic acid groups or with acetic anhydride and pyridine to acetylate amine and hydroxyl functionalities) led to reproducible protein structure modification, as demonstrated by Fourier transform-IR and by pH titration. Hair from BALB/c mice was used. The accumulation of fentanyl was examined in hair samples exposed to fentanyl in methanol or methylene chloride solutions (10 ng/ml, 24 hr). Fentanyl was recovered from hair by 24-hr extraction in phosphate buffer, pH 6. Esterification of hair resulted in significantly less uptake of nonionized fentanyl from a methanolic solution and significantly lower recovery of Drug from hair, relative to untreated hair, suggesting that carboxylic acid functionalities are necessary for the incorporation of Drug. Acetylation of hair resulted in increased removal of fentanyl from methylene chloride solutions and increased recovery of fentanyl. This is consistent with the creation or expansion of a less polar compartment. Fentanyl uptake from a methanolic solution was also greater in acetylated hair. These results demonstrate that solution-accessible ionizable functionalities of hair play a significant role in the accumulation and retention of nonionized fentanyl from organic solutions.
Craig K. Svensson - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulation and Drug Acetylation: influence of the immunomodulator tilorone on hepatic, renal and blood N-acetyltransferase activity and on hepatic cytosolic acetyl coenzyme A content.
Biochemical pharmacology, 1992Co-Authors: Robert K. Drobitch, Mark Tomilo, Craig K. SvenssonAbstract:Abstract The biochemical alteration responsible for immunomodulator enhancement of Drug Acetylation in vivo was probed ex vivo and in vitro in the rat. Rat liver or kidney cytosol, obtained by differential centrifugation, or whole blood served as the source of N-acetyltransferase (NAT). Addition of tilorone (0.5–8.0mM) to incubation mixtures containing procainamide (PA, 0.6mM) and acetyl coenzyme A (AcCoA, 0.42 mM) resulted in the inhibition of N-acetylprocainamide formation, while lower concentrations of tilorone had no effect. Pretreatment of rats with tilorone (50 mg/kg) administered orally 48 hr prior to sacrifice did not alter hepatic apparent Km and Vmax for NAT toward PA compared to control animals. Utilization of an AcCoA regenerating system in the incubation mixtures also resulted in no significant differences in the apparent Michaelis-Menten parameters obtained. Acetylation activity in kidney and whole blood also was not altered by immunomodulator pretreatment. Hepatic cytosolic AcCoA content was reduced significantly 48 hr after tilorone pretreatment (5.10 ± 2.1 vs 11.97 ± 2.2 nmol/mg protein) (P
Peter R. Stout - One of the best experts on this subject based on the ideXlab platform.
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Fentanyl in Hair
Drug Metabolism and Disposition, 1998Co-Authors: Peter R. Stout, Douglas J Claffey, James A. RuthAbstract:The levels of fentanyl extractable from mouse hair after chronic systemic administration and the suitability of externally loaded hair samples for establishing control and comparison samples were determined. Additionally, the effects of chemical modification of specific polar functionalities within the hair protein matrix on the deposition and recovery of fentanyl in hair subjected to external loading were determined. BALB/c mice entering a second phase of synchronized hair growth were treated ip with fentanyl (0.02, 0.05, or 0.10 mg/kg) on Monday, Wednesday, and Friday for 3 weeks. At that time, fentanyl concentrations in hair, as determined by GC/MS, were 0.025–0.050 ng/mg of hair. Hair samples exposed to fentanyl in phosphate buffer (ionized Drug) showed no significant accumulation of Drug into the hair, as determined by loss of fentanyl from the loading solution or by extraction of the hair. Hair samples exposed to nonionized fentanyl in methanolic solution (10, 50, and 100 ng/ml) showed significant accumulation of Drug in the hair and significant removal of Drug from the incubation solution. Fentanyl removal from solution plateaued after 24 hr, suggesting equilibration between fentanyl in solution and fentanyl in the hair. A mass balance between Drug lost from the incubation solution and Drug recovered from hair samples suggests that 94% of accumulated fentanyl is tightly bound to the hair matrix or resides in water-inaccessible compartments within the hair. These results suggest that fentanyl accumulation after in vivo administration differs, in the nature of storage, from fentanyl accumulation from external solutions and that external spiking of hair may not provide suitable control samples. Chemical modification of hair protein functionalities (reaction with diazomethane to esterify carboxylic acid groups or with acetic anhydride and pyridine to acetylate amine and hydroxyl functionalities) led to reproducible protein structure modification, as demonstrated by Fourier transform-IR and by pH titration. Hair from BALB/c mice was used. The accumulation of fentanyl was examined in hair samples exposed to fentanyl in methanol or methylene chloride solutions (10 ng/ml, 24 hr). Fentanyl was recovered from hair by 24-hr extraction in phosphate buffer, pH 6. Esterification of hair resulted in significantly less uptake of nonionized fentanyl from a methanolic solution and significantly lower recovery of Drug from hair, relative to untreated hair, suggesting that carboxylic acid functionalities are necessary for the incorporation of Drug. Acetylation of hair resulted in increased removal of fentanyl from methylene chloride solutions and increased recovery of fentanyl. This is consistent with the creation or expansion of a less polar compartment. Fentanyl uptake from a methanolic solution was also greater in acetylated hair. These results demonstrate that solution-accessible ionizable functionalities of hair play a significant role in the accumulation and retention of nonionized fentanyl from organic solutions.
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Chemical factors involved in accumulation and retention of fentanyl in hair after external exposure or in vivo deposition
Drug Metabolism and Disposition, 1998Co-Authors: Peter R. Stout, Douglas J Claffey, James A. RuthAbstract:The levels of fentanyl extractable from mouse hair after chronic systemic administration and the suitability of externally loaded hair samples for establishing control and comparison samples were determined. Additionally, the effects of chemical modification of specific polar functionalities within the hair protein matrix on the deposition and recovery of fentanyl in hair subjected to external loading were determined. BALB/c mice entering a second phase of synchronized hair growth were treated ip with fentanyl (0.02, 0.05, or 0.10 mg/kg) on Monday, Wednesday, and Friday for 3 weeks. At that time, fentanyl concentrations in hair, as determined by GC/ MS, were 0.025-0.050 ng/mg of hair. Hair samples exposed to fentanyl in phosphate buffer (ionized Drug) showed no significant accumulation of Drug into the hair, as determined by loss of fentanyl from the loading solution or by extraction of the hair. Hair samples exposed to nonionized fentanyl in methanolic solution (10, 50, and 100 ng/ml) showed significant accumulation of Drug in the hair and significant removal of Drug from the incubation solution. Fentanyl removal from solution plateaued after 24 hr, suggesting equilibration between fentanyl in solution and fentanyl in the hair. A mass balance between Drug lost from the incubation solution and Drug recovered from hair samples suggests that 94% of accumulated fentanyl is tightly bound to the hair matrix or resides in water-inaccessible compartments within the hair. These results suggest that fentanyl accumulation after in vivo administration differs, in the nature of storage, from fentanyl accumulation from external solutions and that external spiking of hair may not provide suitable control samples. Chemical modification of hair protein functionalities (reaction with diazomethane to esterify carboxylic acid groups or with acetic anhydride and pyridine to acetylate amine and hydroxyl functionalities) led to reproducible protein structure modification, as demonstrated by Fourier transform-IR and by pH titration. Hair from BALB/c mice was used. The accumulation of fentanyl was examined in hair samples exposed to fentanyl in methanol or methylene chloride solutions (10 ng/ml, 24 hr). Fentanyl was recovered from hair by 24-hr extraction in phosphate buffer, pH 6. Esterification of hair resulted in significantly less uptake of nonionized fentanyl from a methanolic solution and significantly lower recovery of Drug from hair, relative to untreated hair, suggesting that carboxylic acid functionalities are necessary for the incorporation of Drug. Acetylation of hair resulted in increased removal of fentanyl from methylene chloride solutions and increased recovery of fentanyl. This is consistent with the creation or expansion of a less polar compartment. Fentanyl uptake from a methanolic solution was also greater in acetylated hair. These results demonstrate that solution-accessible ionizable functionalities of hair play a significant role in the accumulation and retention of nonionized fentanyl from organic solutions.
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Fentanyl in hair - Chemical factors involved in accumulation and retention of fentanyl in hair after external exposure or in vivo deposition
Drug metabolism and disposition: the biological fate of chemicals, 1998Co-Authors: Peter R. Stout, Douglas J Claffey, James A. RuthAbstract:The levels of fentanyl extractable from mouse hair after chronic systemic administration and the suitability of externally loaded hair samples for establishing control and comparison samples were determined. Additionally, the effects of chemical modification of specific polar functionalities within the hair protein matrix on the deposition and recovery of fentanyl in hair subjected to external loading were determined. BALB/c mice entering a second phase of synchronized hair growth were treated ip with fentanyl (0.02, 0.05, or 0.10 mg/kg) on Monday, Wednesday, and Friday for 3 weeks. At that time, fentanyl concentrations in hair, as determined by GC/MS, were 0.025–0.050 ng/mg of hair. Hair samples exposed to fentanyl in phosphate buffer (ionized Drug) showed no significant accumulation of Drug into the hair, as determined by loss of fentanyl from the loading solution or by extraction of the hair. Hair samples exposed to nonionized fentanyl in methanolic solution (10, 50, and 100 ng/ml) showed significant accumulation of Drug in the hair and significant removal of Drug from the incubation solution. Fentanyl removal from solution plateaued after 24 hr, suggesting equilibration between fentanyl in solution and fentanyl in the hair. A mass balance between Drug lost from the incubation solution and Drug recovered from hair samples suggests that 94% of accumulated fentanyl is tightly bound to the hair matrix or resides in water-inaccessible compartments within the hair. These results suggest that fentanyl accumulation afterin vivo administration differs, in the nature of storage, from fentanyl accumulation from external solutions and that external spiking of hair may not provide suitable control samples. Chemical modification of hair protein functionalities (reaction with diazomethane to esterify carboxylic acid groups or with acetic anhydride and pyridine to acetylate amine and hydroxyl functionalities) led to reproducible protein structure modification, as demonstrated by Fourier transform-IR and by pH titration. Hair from BALB/c mice was used. The accumulation of fentanyl was examined in hair samples exposed to fentanyl in methanol or methylene chloride solutions (10 ng/ml, 24 hr). Fentanyl was recovered from hair by 24-hr extraction in phosphate buffer, pH 6. Esterification of hair resulted in significantly less uptake of nonionized fentanyl from a methanolic solution and significantly lower recovery of Drug from hair, relative to untreated hair, suggesting that carboxylic acid functionalities are necessary for the incorporation of Drug. Acetylation of hair resulted in increased removal of fentanyl from methylene chloride solutions and increased recovery of fentanyl. This is consistent with the creation or expansion of a less polar compartment. Fentanyl uptake from a methanolic solution was also greater in acetylated hair. These results demonstrate that solution-accessible ionizable functionalities of hair play a significant role in the accumulation and retention of nonionized fentanyl from organic solutions.
Robert K. Drobitch - One of the best experts on this subject based on the ideXlab platform.
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Immunomodulation and Drug Acetylation: influence of the immunomodulator tilorone on hepatic, renal and blood N-acetyltransferase activity and on hepatic cytosolic acetyl coenzyme A content.
Biochemical pharmacology, 1992Co-Authors: Robert K. Drobitch, Mark Tomilo, Craig K. SvenssonAbstract:Abstract The biochemical alteration responsible for immunomodulator enhancement of Drug Acetylation in vivo was probed ex vivo and in vitro in the rat. Rat liver or kidney cytosol, obtained by differential centrifugation, or whole blood served as the source of N-acetyltransferase (NAT). Addition of tilorone (0.5–8.0mM) to incubation mixtures containing procainamide (PA, 0.6mM) and acetyl coenzyme A (AcCoA, 0.42 mM) resulted in the inhibition of N-acetylprocainamide formation, while lower concentrations of tilorone had no effect. Pretreatment of rats with tilorone (50 mg/kg) administered orally 48 hr prior to sacrifice did not alter hepatic apparent Km and Vmax for NAT toward PA compared to control animals. Utilization of an AcCoA regenerating system in the incubation mixtures also resulted in no significant differences in the apparent Michaelis-Menten parameters obtained. Acetylation activity in kidney and whole blood also was not altered by immunomodulator pretreatment. Hepatic cytosolic AcCoA content was reduced significantly 48 hr after tilorone pretreatment (5.10 ± 2.1 vs 11.97 ± 2.2 nmol/mg protein) (P
Gerd Geisslinger - One of the best experts on this subject based on the ideXlab platform.
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Drug Acetylation in Liver Disease
Clinical Pharmacokinetics, 1998Co-Authors: Micha Levy, Yoseph Caraco, Gerd GeisslingerAbstract:N -Acetylation is a phase II conjugation reaction mediated in humans by the polymorphic N -acetyltransferase 2 (NAT2) and N -acetyltransferase 1 (NAT1). Acetylation of some Drugs may be modestly decreased in patients with chronic liver disease, whereas acute liver injury has no effect on Drug Acetylation. For NAT2 substrates, the impairment in Acetylation capacity seems to be phenotype-specific, with a more prominent effect being exerted in rapid than slow acetylators. Thus, in the presence of significant hepatic dysfunction, the activity of NAT2 may not exhibit its usual bimodal distribution, and hence phenotypic assignment may not be reliable. Furthermore, it remains to be evaluated whether the precautions advised for slow acetylators when treated with Drugs metabolised by NAT2 apply to all patients (regardless of phenotype) with liver cirrhosis.
