P-糖蛋白抑制剂奎尼丁可降低布比卡因诱发大鼠惊厥的阈值，但对利多卡因诱发的惊厥阈值无影响。

The P-glycoprotein inhibitor quinidine decreases the threshold for bupivacaine-induced, but not lidocaine-induced, convulsions in rats.

作者信息

Funao Tomoharu, Oda Yutaka, Tanaka Katsuaki, Asada Akira

机构信息

Department of Anesthesiology and Intensive Care Medicine, Graduate School of Medicine, Osaka City University, Osaka, Japan.

出版信息

Can J Anaesth. 2003 Oct;50(8):805-11. doi: 10.1007/BF03019376.

DOI:10.1007/BF03019376

PMID:14525819

Abstract

PURPOSE

To examine whether inhibition of P-glycoprotein (P-gp) activity by quinidine affects the central nervous system toxicity of lidocaine and racemic bupivacaine (bupivacaine).

METHODS

Forty male Sprague-Dawley rats were randomly divided into four groups (n = 10). Fifteen minutes following administration of 15 mg x kg(-1) of quinidine (QL and QB groups) or saline (L and B groups), lidocaine (L and QL groups, 4 mg x kg(-1) x min(-1)) or bupivacaine (B and QB groups, 1 mg x kg(-1) x min(-1)) was infused until convulsions occurred. Concentrations of lidocaine and its primary metabolite, monoethylglycinexylidide (MEGX) and bupivacaine in plasma and in the brain at the onset of convulsions were measured by high-performance liquid chromatography.

RESULTS

There were no differences in the dose of lidocaine required to induce convulsions between the L and QL groups. There were no differences in the concentrations of total (L = 17.2 +/- 3.5, QL = 16.6 +/- 2.6 micro g x mL(-1)) or unbound lidocaine (L = 7.8 +/- 2.5, QL = 7.3 +/- 2.3 micro g x mL(-1)), total (L = 1.2 +/- 0.5, QL = 1.3 +/- 0.7 micro g x mL(-1)) or unbound MEGX (L = 0.9 +/- 0.5, QL = 0.8 +/- 0.4 micro g x mL(-1)) in plasma, total lidocaine or MEGX in the brain at the onset of convulsions between the L and QL groups. The dose of bupivacaine required to induce convulsions was comparable in the B and QB groups. At the onset of convulsions, plasma concentrations of both total (B = 4.9 +/- 1.1, QB = 4.0 +/- 0.6 micro g x mL(-1), P = 0.03) and unbound bupivacaine (B = 1.4 +/- 0.6, QB = 0.9 +/- 0.2 micro g x mL(-1), P = 0.02) were significantly lower in the QB group than in the B group. There were no differences in concentration of total bupivacaine in the brain between the B and QB groups.

CONCLUSION

These results suggest that quinidine inhibited P-gp activity, resulting in increased brain/plasma concentration ratio of bupivacaine, but not of lidocaine, and decreased the threshold of plasma concentration for bupivacaine-induced convulsions.

摘要

目的

研究奎尼丁对P-糖蛋白（P-gp）活性的抑制是否会影响利多卡因和消旋布比卡因（布比卡因）的中枢神经系统毒性。

方法

将40只雄性Sprague-Dawley大鼠随机分为四组（n = 10）。在给予15 mg·kg⁻¹奎尼丁（QL组和QB组）或生理盐水（L组和B组）15分钟后，输注利多卡因（L组和QL组，4 mg·kg⁻¹·min⁻¹）或布比卡因（B组和QB组，1 mg·kg⁻¹·min⁻¹）直至惊厥发生。通过高效液相色谱法测定惊厥发作时血浆和脑中利多卡因及其主要代谢产物单乙基甘氨酰二甲苯胺（MEGX）和布比卡因的浓度。

结果

L组和QL组之间诱导惊厥所需的利多卡因剂量没有差异。惊厥发作时，血浆中总利多卡因（L = 17.2 ± 3.5，QL = 16.6 ± 2.6 μg·mL⁻¹）或游离利多卡因（L = 7.8 ± 2.5，QL = 7.3 ± 2.3 μg·mL⁻¹）、总MEGX（L = 1.2 ± 0.5，QL = 1.3 ± 0.7 μg·mL⁻¹）或游离MEGX（L = 0.9 ± 0.5，QL = 0.8 ± 0.4 μg·mL⁻¹）的浓度，以及脑中总利多卡因或MEGX的浓度在L组和QL组之间没有差异。B组和QB组之间诱导惊厥所需的布比卡因剂量相当。惊厥发作时，QB组血浆中总布比卡因（B = 4.9 ± 1.1，QB = 4.0 ± 0.6 μg·mL⁻¹，P = 0.03）和游离布比卡因（B = 1.4 ± 0.6，QB = 0.9 ± 0.2 μg·mL⁻¹，P = 0.02）的浓度均显著低于B组。B组和QB组之间脑中总布比卡因的浓度没有差异。