Increased P-glycoprotein expression and decreased phenobarbital distribution in the brain of pentylenetetrazole-kindled rats.
The purposes of this study were to investigate whether P-glycoprotein (P-GP) is overexpressed in the brain of pentylenetetrazole (PTZ)-kindled rats, and to investigate the effects of P-GP up-regulation on the distribution of phenobarbital (PB) in brain and its antiepileptic effects. Kindled rats were developed using a subconvulsive dose of PTZ (30 mg/kg, once every 2 days, i.p.) for 24 days. P-GP expression and function were measured by Western blot analysis and rhodamine 123 (Rho 123) distribution in brain. Kindled rats received 10 mg/kg of PB alone or co-administration of cyclosporine A (CsA, 5 mg/kg). At 60 min after administration of PB, concentrations of PB in brain and plasma were measured and the tissue-to-plasma concentration ratios of PB were calculated. Anticonvulsive effects of PB (13.2 mg/kg) alone or co-administration of CsA on the kindled rats were observed. The results showed that kindling resulted in 1.7-fold increase of P-GP level in brain, accompanied by significant decrease of tissue-to-plasma concentration ratios of Rho 123 and PB in hippocampus and cortex without affecting their concentrations in plasma. Co-administration of CsA reversed the decrease of PB concentration in brain without affecting PB level in plasma and significantly potentiated the anticonvulsive effects of PB. The present study demonstrated that chronic PTZ-kindling might increase P-GP expression and function in brain of rat, resulting in decrease of Rho 123 and PB levels in brain tissues. Co-administration of CsA increased PB levels in brain and enhanced anticonvulsive effects of PB by inhibiting P-GP function.
Liu
Xiaodong
X
Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China. xdliu@cpu.edu.cn
Yang
Zhihong
Z
Yang
Jiansong
J
Yang
Huiwen
H
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology*; D004827:Epilepsy / Q000139:chemically induced / Q000523:psychology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*; D007608:Kainic Acid / Q000494:pharmacology; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D010433:Pentylenetetrazole / Q000494:pharmacology*; D010634:Phenobarbital / Q000493:pharmacokinetics*; D010862:Pilocarpine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D015854:Up-Regulation / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003292:Convulsants; D018690:Excitatory Amino Acid Agonists; D006993:Hypnotics and Sedatives; D018721:Muscarinic Agonists; D010862:Pilocarpine; D020112:Rhodamine 123; D007608:Kainic Acid; D010433:Pentylenetetrazole; D010634:Phenobarbital