EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS 2007, Vol. 32, No.2, pp. 109-117 Effect of cholic acid and its keto derivatives on the anal- gesic action of lidocaine and associated biochemical pa- rameters in rats MIHALJ POSAt, SLAVKO KEVRESAN 3 , MOMIR MIKOV\ VERA CIRIN-NOVTA 2 , KSENIJA KUHAJDA 2 'Departrnent of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Republic of Serbia, 2Faculty of Sciences, University of Novi Sad, Novi Sad, Republic of Serbia, 3Faculty of Agriculture, University of Novi Sad, Novi Sad, Republic of Serbia, "School ofPhannacy, Otago University, Dunedin, New Zealand Receivedfor publication: April 2, 2007 Key words: Cholic acid, cholic acid keto derivatives, micelles, mixed micelles, lidocaine, local anesthesia SUMMARY This study examined the effect of the structure and concentration of cholic acid and its keto derivatives on the local analgesic action of lidocaine in rats, measured by an analgesimetric method. The increase in bile acid concentrations in the administered lidocaine solution increased the duration of local anesthesia. It was found that the introduction of keto groups into the cholic acid molecule yielded derivatives with lower promotory action, i.e. decreased the duration of local anesthesia. The biochemical parameters investi- gated indicated that the keto derivatives of cholic acid exhibited no toxicity compared to that of cholic acid itself. 'INTRODUCTION In aqueous solutions, bile acid molecules aggregate and form micelles which may include cholesterol, phospholipids and hydrophobic drugs (1). Bile acids are used as additives to pharmaceutical drugs to in- crease their solubility, where their promotory action has been observed in the transport of peptides across the nasal mucosae (2-5). As regards insulin transport through the lipid barrier and, the enhancement of insulin nasal absorption, the promotory effect of acid is of particular importance (6). . Please send reprint requests to: Slavko Kevresan, Faculty of Agriculture, University of Novi Sad, Trg Dositeja Obradovica 8,21000 Novi Sad, Republic of Serbia, tel: +381214853272 fax: +38121450857; E-mail: kevresan@poli.ns.ac.vu It has been found that the administration of the so- dium salt of acid and its methyl ester potentiates the hypnotic effect of pentobarbital, as well as the analgesic effect of morphine (7). An explanation regarding the pro- motory effect of bile acids on the action of polar drugs has been given by Gordon ey al. and by Carey and Small (8,9). These authors surmised that bile acids could be incorporated into the membrane where, at a certain concentration, they could form reverse micelles that included water molecules, thus creating hydrophilic pores in the cell membrane. It has been assumed that the analgesic effect of bile acids is probably due to their membrane-stabilizing action. Thus, for example, sodium glycodeoxycholate administered in combination with macrolide antibi- otics reduces the pain experienced on intravenous (i.v.) infusion (10).