RT Journal Article
SR Electronic
T1 Effect of P-Glycoprotein on the Pharmacokinetics and Tissue Distribution of Enaminone Anticonvulsants: Analysis by Population and Physiological Approaches
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1096
OP 1104
DO 10.1124/jpet.102.035436
VO 302
IS 3
A1 Donna S. Cox
A1 Kenneth R. Scott
A1 Huanling Gao
A1 Natalie D. Eddington
YR 2002
UL http://jpet.aspetjournals.org/content/302/3/1096.abstract
AB Multidrug resistance (MDR), mediated by P-glycoprotein (Pgp) has been identified as altering the disposition of structurally diverse compounds. Previous in vitro studies in bovine brain microvascular endothelial cells and MCF/Adr [Adriamycin (doxorubicin)-resistant human breast cancer] cells displayed that the transport of enaminone anticonvulsants was influenced by Pgp. Therefore the objectives of this study was to further evaluate the influence of Pgp on the pharmacokinetics and tissue distribution of the enaminone analogs. mdr1ab (+/+) and mdr1ab (−/−) male mice (20 ± 5 g) were administered DM5 (methyl 4-[(4′-chlorophenyl)amino]-6-methyl-2-oxo-3-cyclohexene-1-carboxylate) or DM44 (12.5 mg/kg, i.v.). Cohorts (n = 3) were sacrificed over a 12-h period, and samples were analyzed by a validated UV-high performance liquid chromatography assay method. Population analysis was used to estimate pharmacokinetic parameters and partition coefficients were determined for tissues. The clearance (0.51 versus 0.33 l/h/kg) and Vd (1.25 versus 0.93 l/kg) of DM5 were found to be higher (p < 0.05), however the area under the curve (26.1 versus 38.2 μg/ml · h) was lower (p < 0.05) in mdr1a/1b(−/−) versus mdr1a/1b (+/+) mice, respectively. Similar findings were observed for DM44. Tissues known to express Pgp such as the heart, liver, lung, and brain displayed 2-fold or higher tissue levels in mdr1a/1b (−/−) versusmdr1a/1b (+/+) mice. These results strongly suggest that Pgp may influence enaminone tissue distribution and pharmacokinetics and may play a significant role in the effective treatment of epilepsy with these analogs. The American Society for Pharmacology and Experimental Therapeutics