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Pharmacokinetics and bioavailability of a newly synthesized dihydropyridine compound with multidrug resistance reversal activity
Author(s) -
Zhou Xiaofei,
MacDiarmid Joan,
Coburn Robert A.,
Morris Marilyn E.
Publication year - 2005
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.460
Subject(s) - bioavailability , pharmacokinetics , pharmacology , dihydropyridine , chemistry , oral administration , volume of distribution , p glycoprotein , multiple drug resistance , medicine , calcium , biochemistry , organic chemistry , antibiotics
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.