Abstract |
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.
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Authors | Wei Yin, Liang-Shang Gan, Jing-Tao Wu, Suresh K Balani, Hua Yang, Frank W Lee |
Journal | Drug metabolism letters
(Drug Metab Lett)
Vol. 1
Issue 3
Pg. 195-8
(Aug 2007)
ISSN: 1874-0758 [Electronic] United Arab Emirates |
PMID | 19356043
(Publication Type: Journal Article)
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Chemical References |
- Receptor, Melanocortin, Type 4
- Ethane
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Topics |
- Administration, Oral
- Animals
- Area Under Curve
- Brain
(metabolism)
- Cachexia
(drug therapy, physiopathology)
- Drug Delivery Systems
- Ethane
(administration & dosage, analogs & derivatives, pharmacokinetics)
- Injections, Intravenous
- Male
- Rats
- Rats, Wistar
- Receptor, Melanocortin, Type 4
(antagonists & inhibitors)
- Time Factors
- Tissue Distribution
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