Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches.
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 V(d) (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 microg/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 (-/-) versus mdr1a/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.
Pharmacokinetics Biopharmaceutics Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 100 Penn Street, Baltimore, MD 21201, USA.
Donna S
DS
Cox
Kenneth R
KR
Scott
Huanling
H
Gao
Natalie D
ND
Eddington
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D003512:Cyclohexanones / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011153:Population; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000814:Aniline Compounds; D000927:Anticonvulsants; D003512:Cyclohexanones; C420449:DM5 compound