EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS 2008, Vol. 33, No.2, pp. 77-84 Influence of sodium monoketocholate on the hypolipi- demic activity of lovastatin in healthy and diabetic rats SUNCICA KOJIC-DAMJANOV 1 *, MIRJANA DJERIC 1 , MOMIR MIKOV 2 , KSENUA KU- HAJDA 3 and SLAVKO KEVRESAN 4 'Institute of Laboratory Medicine, Clinical Center of Voivodina, Novi Sad, Republic of Serbia; 20epartment of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Republic of Serbia; 30epartment of Chemistry, Faculty of Sciences, University of Novi Sad, Republic of Serbia; 4Faculty of Agriculture, University of Novi Sad, Republic of Serbia Receivedfor publication: November 19,2007 Key words: Lipids, hypolipidemic therapy, synthetic bile salt, sodium Ｓ｡ＬＷ｡Ｍ､ｩｨｹ､ｲｯｸｹＭＱＲＭｫ･ｴｯＭＵｾﾭ cholanate (Na-MKHA), lovastatin, rat SUMMARY Recent findings regarding the physiological transport mechanisms and metabolism of bile acids have led to an increased interest in their synthetic derivatives, especially as transmucous transporters. The aim of this study was to examine the influence of the syn- thetic sodium salt of monoketocholic acid (Na-MKHA) on the hypolipidemic activity of lovastatin. The effects of a 7 days admini- stration of lovastatin (20 mg/kg b.w.) (experimental group I, n=5) and a combination of lovastatin (20 rug/kg b.w.) and Na-MKHA (2 mg/kg b.w.) (experimental group 2, n=5) in group of healthy and diabetic male Wistar rats were investigated. The animals in the control group of healthy (n=5) and diabetic (n=5) rats were treated with physiological saline (10 mlIkg b.w.) per os twice a day. In the healthy rats, lovastatin increased the low density lipoprotein (LDL) (32.14%) and non-high density lipoprotein (HDL) (15.38%) cholesterol and decreased HDL cholesterol levels (9.89%), and also increased the investigated atherogenic ratios. Na-MKHA sig- nificantly potentiated lovastatin activity, and its effects on the LDL (p<0.05; 102.70%), HDL (p<0.01; 32.93%) and non-HDL (p<0.05; 65%) cholesterol levels, as well as the LDUHDL (p<0.02; 231.11%), total cholesterollHDL (p<0.02; 70.52%) and non- HDUHDL cholesterol ratios (p<0.02; 167.12%). In diabetic animals, the potentiating effect of Na-MKHA was not significant. The stimulatory effect of Na-MKHA is probably a consequence of the intensified transmembrane transport of lovastatin due to the direct action of bile acids on the cell membranes, as well as a result of their enhanced transport via specific bile acid transport systems. INTRODUCTION In recent years, particular attention has been paid to the synthesis of new metabolites of bile acids, as it appears that some of them might be of potential pharmacological importance. It has been found that they can significantly improve the pharmacokinetic Please send reprint requests to: Suncica Kojic-Damjanov, Institute of Laboratory Medicine, Clinical Center of Voivodina, Hajduk Veljkova I, 21000 Novi Sad, Serbia; e- mail: s.kojic@neobee.net and pharmacodynamic properties of certain drugs (1) and modify the genetic expression (2,3) and activity of certain enzymes (4). Bile acids and their synthetic metabolites have gained pharmacological signifi- cance as membrane-stabilizing ciliotoxic agents (5- 7). Their detergent-like action on biological mem- branes (5,8,9), has encouraged intensive studies on these compounds as transport promoters through the mucous membrane (10,11), primarily their stimula- tory effect on the nasal absorption of certain drugs (12,13). Of special interest is the increased absorp- tion of peptide-based drugs, resulting from structural