Effects of plateau hypoxia on pharmacokinetic parameters and cerebral-blood distribution of levetiracetam in rats.

Abstract

Plateau hypoxia exposure causes changes in pharmacokinetic parameters and cerebral-blood distribution of drugs, including many substrates of P-glycoprotein (P-gp). Levetiracetam, a kind of antiepileptic drugs, is a substrate of P-gp. Whether plateau hypoxia exposure changes its pharmacokinetic characteristics and cerebral-blood distribution remains unclear. This study aims to investigate the effects of plateau hypoxia on the pharmacokinetics and cerebra-blood distribution of levetiracetam. Wistar rats were divided into a low-altitude control group, a high-altitude group, a solvent group, and a P-gp induction group. After 24 h of exposure at altitude of 4 010 m, rats in the high-altitude group were given levetiracetam orally or intravenously. The plasma was respectively collected at 0.083, 0.25, 0.5, 0.83, 1.25, 2, 4, 6, 8, 10, 12, and 24 h after oral administration of the drug, while both plasma and brain were respectively collected at 5, 45, 60,120 and 240 min after intravenous injection. After 3 days administration of dexamethasone, plasma and brain of rats in the P-gp induction group were collected at 120 min after intravenously giving levetiracetam. Plasma and brain concentrations of the drug were determined by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The expression of P-gp in blood-brain barrier was detected by Western blotting. Compared with the low-altitude control group, the area under the curve (AUC) and mean residence time (MRT) of levetiracetam were respectively decreased by 14.69% (P<0.01) and 15.42% (P<0.01), while the clearance (CL) was increased by 16.67% (P<0.01) in the high-altitude group. The ratio of brain/blood plasma drug concentration was decreased by 22.82% (P<0.05), 12.42% (P<0.05), 17.40% (P<0.01), and 13.22% (P<0.01) at 5, 45, 120, and 240 min after injection, respectively. The expression of P-gp on the blood-brain barrier was increased by 86.3% (P<0.05). Compared with the solvent control group, the expression of P-gp on the blood-brain barrier in the P-gp induction group was increased by 56.3% (P<0.05), the ratio of brain/blood plasma drug concentration was decreased by 19.3% (P<0.05). After acute plateau hypoxia exposure, the pharmacokinetic of levetiracetam in rats are altered, and the cerebral-blood distribution of the drug in rats is decreased, which may be related to the up-regulation of P-gp expression on the blood-brain barrier.