Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]

Publication Date:
2018-06-02
Publisher:
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Print ISSN:
0090-9556
Electronic ISSN:
1521-009X
Topics:
Chemistry and Pharmacology
Medicine
Published by:
http://www.aspet.org/
_version_ 1836398954532569088
autor Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
beschreibung To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers ( n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was 〈25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.
citation_standardnr 6273783
datenlieferant ipn_articles
feed_id 1915
feed_publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
feed_publisher_url http://www.aspet.org/
insertion_date 2018-06-02
journaleissn 1521-009X
journalissn 0090-9556
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
quelle Drug Metabolism and Disposition
relation http://dmd.aspetjournals.org/cgi/content/short/46/7/943?rss=1
search_space articles
shingle_author_1 Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
shingle_author_2 Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
shingle_author_3 Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
shingle_author_4 Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
shingle_catch_all_1 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers ( n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.
Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_2 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers ( n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.
Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_3 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers ( n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.
Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_4 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic ( n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers ( n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 ± 8.3, 32.3 ± 12.8, vs. 51.1 ± 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations.
Prasad, B., Bhatt, D. K., Johnson, K., Chapa, R., Chu, X., Salphati, L., Xiao, G., Lee, C., Hop, C. E. C. A., Mathias, A., Lai, Y., Liao, M., Humphreys, W. G., Kumer, S. C., Unadkat, J. D.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_title_1 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
shingle_title_2 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
shingle_title_3 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
shingle_title_4 Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
timestamp 2025-06-30T23:35:16.607Z
titel Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
titel_suche Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study [Articles]
topic V
WW-YZ
uid ipn_articles_6273783