An evaluation of a C-glucuronide as a liver targeting group: conjugate of a glucocorticoid antagonist.
A beta-C-glucuronide conjugate of the glucocorticoid receptor antagonist, Mifepristone 1, was prepared which maintained binding affinity, had modest in vitro activity, and was metabolically more stable than the parent. Pharmacokinetic studies suggest that the conjugate is recognized by the liver like O-glucuronides and may undergo a portion of the enterohepatic recirculation loop.
Sorensen
Bryan K
BK
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, 60064, Abbott Park, IL, USA. bryan.k.sorensen@abbott.com
Link
J T
JT
von Geldern
Thomas
T
Emery
Maurice
M
Wang
Jiahong
J
Hickman
Bach
B
Grynfarb
Marlena
M
Goos-Nilsson
Annika
A
Carroll
Sherry
S
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D003907:Dexamethasone / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D004764:Enterohepatic Circulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005938:Glucocorticoids / Q000493:pharmacokinetics; D020719:Glucuronides / Q000378:metabolism* / Q000493:pharmacokinetics; D006727:Hormone Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects*; D008862:Microsomes, Liver / Q000378:metabolism; D015735:Mifepristone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D014444:Tyrosine Transaminase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D020719:Glucuronides; D006727:Hormone Antagonists; D007202:Indicators and Reagents; D000644:Quaternary Ammonium Compounds; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D003907:Dexamethasone; C009405:tetrabutylammonium; D014444:Tyrosine Transaminase; D000469:Alkaline Phosphatase