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Pharmacokinetics and bioavailability of a newly synthesized dihydropyridine compound with multidrug resistance reversal activity
- Source :
- Biopharmaceuticsdrug disposition. 26(7)
- Publication Year :
- 2005
-
Abstract
- (+/−)3-(3-(4,4-diphenylpiperidin-1-yl)propyl) 5-methyl 4-(3,4-dimethoxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate ((±)-DHP-014), is a new 4-aryl-1,4-dihydropyridine that can reverse multidrug resistance mediated by the ATP-binding cassette (ABC) transport proteins, P-glycoprotein, multidrug resistance-associated protein 1 and breast cancer resistance protein; it exhibits negligible calcium channel blocking activity. The objective of this work was to investigate the pharmacokinetics of this new compound in rats. Three intravenous (1, 2 and 5 mg/kg) and two oral (25 and 50 mg/kg) doses were administered to female Sprague-Dawley rats. A two-compartment model with nonlinear elimination best characterized the pharmacokinetic profiles after intravenous and oral administration in rats. The terminal half-life of (±)-DHP-014 increased and the systemic clearance significantly decreased at higher doses, indicating nonlinear elimination. The dose-dependent clearance is likely due to saturation of metabolism. The apparent volume of distribution of (±)-DHP-014 was 2.0 L/kg in rats and was unchanged with increasing intravenous doses of (±)-DHP-014. The estimated oral bioavailability of (±)-DHP-014 was 8.2%. The poor bioavailability is likely due to the poor solubility of the compound, as well as to substantial first-pass elimination. Copyright © 2005 John Wiley & Sons, Ltd.
- Subjects :
- Dihydropyridines
Abcg2
Pharmaceutical Science
Biological Availability
Pharmacology
Rats, Sprague-Dawley
Pharmacokinetics
Oral administration
medicine
Animals
Pharmacology (medical)
Volume of distribution
biology
Dose-Response Relationship, Drug
Chemistry
Dihydropyridine
Biological activity
General Medicine
Metabolism
Drug Resistance, Multiple
Bioavailability
Rats
Solubility
Area Under Curve
Data Interpretation, Statistical
Injections, Intravenous
biology.protein
Female
Indicators and Reagents
medicine.drug
Subjects
Details
- ISSN :
- 01422782
- Volume :
- 26
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Biopharmaceuticsdrug disposition
- Accession number :
- edsair.doi.dedup.....063600ef1adfbe6b333b7c146ea5eabf