Disposition of quinine and its major metabolite, 3-hydroxyquinine in patients with liver diseases

Abstract

Quinine, extensively metabolized by CYP 3A4, has 3-hydroxyquinine as the major metabolite which also contributes to its antimalarial activity. This study assessed the impact of various liver diseases on the disposition of quinine and 3-hydroxyquinine. Ten adult patients with liver diseases ranging from cirrhosis, primary liver carcinoma, hepatitis, ascites, and amoebic liver disease as well as six healthy subjects received single oral dose of 600 mg quinine sulphate tablets. Venous blood and urine were collected over 48 h. Quinine and 3-hydroxyquinine were determined from the matrices by a validated high performance liquid chromatography (HPLC) method. Wide inter-individual variations were observed in the subjects especially those with liver diseases. Cmax (4.47 vs 2.41mcg/ml) and AUC (73 vs 51mcg.h/ml) values were significantly increased in liver disease patients. Clearance was reduced by 30% from 3.27 to 2.31 (p = 0.009). Metabolic ratio of quinine/3-hydroxyquinine in plasma decreased from 5.5 to 1.42 over 4 to 48 h. Cumulative amount of quinine and 3-hydroxyquinine produced in urine were 38 mg (8%) and 32 mg (7%) respectively. Compromised metabolism of quinine in liver disease patients suggests the necessity of reviewing the dosage of quinine in liver disease patients who come up with malaria, a situation that further reduces liver function.