Kotsiou A, Tsamouri M, Anagnostopoulou S, Tzivras M, Vairactaris E, Tesseromatis C
Department of Pharmacology, Medical School, University of Athens, Greece.
Eur J Drug Metab Pharmacokinet. 2006 Apr-Jun;31(2):97-101. doi: 10.1007/BF03191125.
Liver disease alters the pharmacokinetic and pharmacodynamic properties of hepatically eliminated drugs. The main factors influenced are plasma albumin levels, enzyme balance (induction & inhibition) and drug binding to tissue proteins. The influence of lidocaine on serum, heart and liver propranolol levels in Wistar rats after liver injury induced by carbon tetrachloride CCl4 0.4 ml/kg x 2/wkl, was investigated. 40 male Wistar rats were divided into four groups (I, II, III, IV; n=10), Group I animals received only propranolol (labelled + cold substance) 40 mg/kg/12 h p.o., group II propranolol plus lidocaine in a single dose of 4mg/kg s.c., group III was treated with CCl4 for 6 weeks and received propranolol x2 at the same dosage as group I, while group VI was treated with CCl4 and the same drug dosage as group II. The simultaneous administration of H3-propranolol and lidocaine increased propranolol levels in the serum and tissues. The liver in damaged animals showed an increase of propranolol level under lidocaine co-administration, probably due to CCl4 induced liver enzyme activity, resulting in a rapid propranolol metabolism or to competition between both drug protein binding sites. The increased propranolol levels in the heart after lidocaine administration were probably due to attributed to its high affinity for heart tissue. Consequently, as regards the therapeutic approach for patients with liver disease receiving propranolol their propranolol dosage should be reduced when lidocaine is co-administered.
肝脏疾病会改变经肝脏消除的药物的药代动力学和药效学特性。主要受影响的因素包括血浆白蛋白水平、酶平衡（诱导与抑制）以及药物与组织蛋白的结合。研究了四氯化碳（CCl4，0.4 ml/kg×2次/周）诱导肝损伤后，利多卡因对Wistar大鼠血清、心脏和肝脏中普萘洛尔水平的影响。40只雄性Wistar大鼠分为四组（I、II、III、IV组；n = 10），I组动物仅口服给予普萘洛尔（标记物 + 冷物质）40 mg/kg/12小时，II组给予普萘洛尔加单次皮下注射4 mg/kg利多卡因，III组用CCl4处理6周，并按与I组相同的剂量给予普萘洛尔×2次，而IV组用CCl4处理并给予与II组相同的药物剂量。同时给予H3 - 普萘洛尔和利多卡因会增加血清和组织中的普萘洛尔水平。在受损动物中，肝脏在利多卡因共同给药的情况下普萘洛尔水平升高，可能是由于CCl4诱导的肝酶活性，导致普萘洛尔快速代谢，或者是由于两种药物蛋白结合位点之间的竞争。利多卡因给药后心脏中普萘洛尔水平升高可能归因于其对心脏组织的高亲和力。因此，对于接受普萘洛尔治疗的肝病患者，当同时给予利多卡因时，应减少普萘洛尔的剂量。
