An indirect screen for brain uptake of 1,2-diarylethane melanocortin 4 receptor antagonists in rats.
Antagonism of the melanocortin 4 receptor (MC4R) has been proposed as a therapeutic intervention for the prevention of lean body mass waste, as in cachexia. Pharmacokinetic profiles of substituted 1,2-diarylethane MC4R antagonists were determined in rats after a single intravenous (IV) administration at 1 mg/kg. Brain and plasma concentrations of these compounds were determined at 1 and 4 hours after an oral dose at 10 mg/kg, since oral administration is the intended clinical dosing route and the pharmacological target is the central nervous system. The brain to plasma concentration ratios (0.10 - 50) after oral dosing correlated well with Vd(ss) (2.21 to 81.4 L/kg; R(2)=0.810) determined after IV administration. A good correlation was also observed between the brain AUC(0-4 hr) (119 - 18400 nM*hr) and Vd(ss) (R(2)=0.981). Thus, further screening and ranking of substituted 1,2-diarylethanes for their brain uptakes could be carried out more efficiently via the simple and indirect Vd(ss) screen after intravenous administration in rats.
Yin
Wei
W
Drug Metabolism and Pharmacokinetics, Non-Clinical Development Sciences, Millennium Pharmaceuticals, Inc., 40 Landsdowne Street, Cambridge, Massachusetts 02139, USA. wyin@mpi.com
Gan
Liang-Shang
LS
Wu
Jing-Tao
JT
Balani
Suresh K
SK
Yang
Hua
H
Lee
Frank W
FW
D000284:Administration, Oral; D000818:Animals; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002100:Cachexia / Q000188:drug therapy / Q000503:physiopathology; D016503:Drug Delivery Systems; D004980:Ethane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014018:Tissue Distribution
D044105:Receptor, Melanocortin, Type 4; D004980:Ethane