Attenuated function and expression of P-glycoprotein at blood-brain barrier and increased brain distribution of phenobarbital in streptozotocin-induced diabetic mice.
The aim of the study was to investigate whether diabetes mellitus modulated the function and expression of P-glycoprotein and the distribution of phenobarbital in the brain of 3-week streptozotocin-induced diabetic mice. P-glycoprotein function in blood-brain barrier was assessed by measuring the brain-to-plasma concentration ratios of rodamine123, a well-known P-glycoprotein substrate, in non-diabetic mice and diabetic mice. P-glycoprotein expression in the brain cortex was evaluated with western blot. Whether diabetes mellitus changed the distribution of phenobarbital (60 mg/kg, i.v.) in brain of mice was measured, and whether the changed distribution caused the difference of phenobarbital (80 and 100 mg/kg) -induced loss of the righting reflex in non-diabetic and diabetic mice were also investigated. The results showed that the brain-to-plasma concentration ratio value of rodamine123 in diabetic mice was significantly higher than that of non-diabetic mice, western blot suggested that the protein level of P-glycoprotein in the brain of 3-week diabetic mice was significantly lower than that of non-diabetic mice, and insulin treatment restored the impairment of P-glycoprotein. The exposure of phenobarbital in brain of diabetic mice was 1.30-fold of that of non-diabetic mice, while in plasma the fold was 1.09. The increased distribution of phenobarbital in the brain of diabetic mice significantly increased the duration of phenobarbital-induced loss of the righting reflex and reduced the latency time of loss of the righting reflex. All the results suggested that the function and expression of P-glycoprotein might be impaired and the brain distribution of phenobarbital was increased in brain of streptozotocin-induced diabetic mice.
Liu
HaiYan
H
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China.
Zhang
DongMei
D
Xu
Xiao
X
Liu
XiaoDong
X
Wang
GuangJi
G
Xie
Lin
L
Pang
XiaoYan
X
Liu
Li
L
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism / Q000503:physiopathology*; D015153:Blotting, Western; D001921:Brain / Q000503:physiopathology; D002492:Central Nervous System Depressants / Q000493:pharmacokinetics* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010634:Phenobarbital / Q000493:pharmacokinetics* / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects / Q000502:physiology; D012018:Reflex / Q000187:drug effects / Q000502:physiology; D013311:Streptozocin; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002492:Central Nervous System Depressants; D013311:Streptozocin; D010634:Phenobarbital