Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]

Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
Published 2018
Publication Date:
2018-01-12
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:
_version_ 1836398745510477825
autor Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
beschreibung Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP’s analgesic activity and 10 times BUP’s respiratory depression effect. To optimize BUP’s dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ~2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ~2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ~50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ~2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.
citation_standardnr 6137002
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feed_publisher The American Society for Pharmacology and Experimental Therapeutics (ASPET)
feed_publisher_url http://www.aspet.org/
insertion_date 2018-01-12
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/46/2/100?rss=1
search_space articles
shingle_author_1 Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
shingle_author_2 Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
shingle_author_3 Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
shingle_author_4 Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
shingle_catch_all_1 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP’s analgesic activity and 10 times BUP’s respiratory depression effect. To optimize BUP’s dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ~2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ~2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ~50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ~2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.
Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_2 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP’s analgesic activity and 10 times BUP’s respiratory depression effect. To optimize BUP’s dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ~2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ~2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ~50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ~2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.
Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_3 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP’s analgesic activity and 10 times BUP’s respiratory depression effect. To optimize BUP’s dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ~2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ~2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ~50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ~2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.
Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_catch_all_4 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
Norbuprenorphine (NBUP) is the major active metabolite of buprenorphine (BUP) that is commonly used to treat opiate addiction during pregnancy; it possesses 25% of BUP’s analgesic activity and 10 times BUP’s respiratory depression effect. To optimize BUP’s dosing regimen during pregnancy with better efficacy and safety, it is important to understand how pregnancy affects NBUP disposition. In this study, we examined the pharmacokinetics of NBUP in pregnant and nonpregnant mice by administering the same amount of NBUP through retro-orbital injection. We demonstrated that the systemic clearance (CL) of NBUP in pregnant mice increased ~2.5-fold compared with nonpregnant mice. Intrinsic CL of NBUP by glucuronidation in mouse liver microsomes from pregnant mice was ~2 times greater than that from nonpregnant mice. Targeted liquid chromatography tandem-mass spectrometry proteomics quantification revealed that hepatic Ugt1a1 and Ugt2b1 protein levels in the same amount of total liver membrane proteins were significantly increased by ~50% in pregnant mice versus nonpregnant mice. After scaling to the whole liver with consideration of the increase in liver protein content and liver weight, we found that the amounts of Ugt1a1, Ugt1a10, Ugt2b1, and Ugt2b35 protein in the whole liver of pregnant mice were significantly increased ~2-fold compared with nonpregnant mice. These data suggest that the increased systemic CL of NBUP in pregnant mice is likely caused by an induction of hepatic Ugt expression and activity. The data provide a basis for further mechanistic analysis of pregnancy-induced changes in the disposition of NBUP and drugs that are predominately and extensively metabolized by Ugts.
Liao, M. Z., Gao, C., Phillips, B. R., Neradugomma, N. K., Han, L. W., Bhatt, D. K., Prasad, B., Shen, D. D., Mao, Q.
The American Society for Pharmacology and Experimental Therapeutics (ASPET)
0090-9556
00909556
1521-009X
1521009X
shingle_title_1 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
shingle_title_2 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
shingle_title_3 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
shingle_title_4 Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
timestamp 2025-06-30T23:31:58.176Z
titel Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
titel_suche Pregnancy Increases Norbuprenorphine Clearance in Mice by Induction of Hepatic Glucuronidation [Articles]
topic V
WW-YZ
uid ipn_articles_6137002