Reduction of cardiovascular and thyroxine-suppressing activities of L-T3 by liver targeting with cholic acid.
This study was designed to determine whether the conjugation product of L-T3 with cholic acid would result in a liver-targeted compound (CGH 509A) with hypocholesterolemic (HC) activity significantly dissociable from cardiovascular (CV) and thyroxine-suppressing (TS) effects normally observed with thyroid hormone. Evaluation of HC activity in lipemic rats showed that CGH 509A was 6 times less potent than L-T3 with ED25 values estimated at 150 and 25 nmol/kg, respectively. CV function measured as changes in atrial rate, atrial tension and heart weight was determined in euthyroid rats. CGH 509A was at least 64 times less cardio-stimulant than L-T3 with minimum effective doses estimated at 2350 and 37 nmol/kg, respectively. TS activity was assessed in euthyroid rats as the potency of any compound to reduce plasma T4 levels. CGH 509A was 50 times less potent than-L-T3 with ED50 values estimated at 900 and 18 nmol/kg, respectively. From these results, it is clear that, while L-T3 was equally potent on HC, CV and TS activities, the HC potency of CGH 509A was at least 15 and 6 times greater than its CV and TS potencies, respectively.
Stephan
Z F
ZF
Research Department, CIBA-GEIGY Corp., Summit, NJ 07901.
Yurachek
E C
EC
Sharif
R
R
Wasvary
J M
JM
Steele
R E
RE
Howes
C
C
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D019826:Cholic Acid; D002793:Cholic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D013974:Thyroxine / Q000037:antagonists & inhibitors*; D014284:Triiodothyronine / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D002793:Cholic Acids; D011988:Receptors, Thyroid Hormone; D014284:Triiodothyronine; D002784:Cholesterol; D019826:Cholic Acid; D013974:Thyroxine