EUROPEAN JOURNAL OF DRUG METABOLISM AND PHARMACOKINETICS 2007, Vol. 32, No.1, pp. 7-12 Bioavailability and hypoglycemic activity of the semisynthetic bile acid salt, sodium 3u,7a-dihydroxy- in healthy and diabetic rats M. MIKOV\ N.S. BONI \ H. AL-SALAMI\ K. KUHAJDA 2 , S. KEVRESAN 3 , S. GOLOCORBIN-KOW, J.P. FAWCETT! 'School of Pharmacy, University of Otago, Dunedin, New Zealand; 2Department of Biochemistry, Faculty of Sciences, University of Novi Sad, Serbia; 3Department of Chemistry, Faculty of Agriculture, University of Novi Sad, Serbia; "Departrnent of Pharmacology and Toxicology, Faculty of Medicine, University of Novi Sad, Serbia Receivedfor publication: May 12, 2006 Key words: Bile acid, sodium (MKC); glucose; pharmacokinetics; bioavailability, rat SUMMARY Previous studies in our laboratory have shown that the semisynthetic bile acid derivative, sodium 3a.7a-dihydroxy-12-oxo-5J3- cholanate (MKC), has hypoglycemic activity. The aim of this study was to investigate the relationship between the pharmacokinetics and hypoglycemic activity of MKC in healthy and diabetic rats. Groups of healthy and alloxan-induced diabetic rats were dosed intravenously (i.v.) and orally with MKC (4 mg/kg). Blood samples were taken before administration of the dose and at 20, 40, 60, 80, 120. 150. 180, 210 and 240 minutes post-dose. MKC serum concentration was measured by HPLC, and pharmacokinetic parameters determined using the WinNonlin program. The absolute bioavailability of MKC was found to be low in healthy and diabetic rats (29 and 23% respectively) and was not significantly different between the two groups. Mean residence time (MRT), volume of distribution (V ct ) and half-life (t ll2 ) ofMKC after oral administration were significantly lower in diabetic than in healthy rats (21,31 and 29% respectively). After the i.v, dose. the change in blood glucose concentration was not significant in either healthy or diabetic rats. After the oral dose, the decrease in blood glucose concentration was significant, reaching a maximum decrease from baseline of 24% in healthy rats and 15% in diabetic rats. The results suggest that a first-pass effect is crucial for the hypoglycemic activity of MKC. indicating that a metabolite of MKC and/or interference with metabolism and glucose transport is responsible. INTRODUCTION Bile acids and their salts are constituents of bile and are classified as primary and secondary. Cholic and Please send reprint requests to: Prof. Dr. Momir Mikov, School of Pharmacy, University of Otago. PO Box 913, Dunedin 9054, New Zealand chenodeoxycholic acids are the most abundant pri- mary bile acids in human bile. Within the intestine, primary bile acids are convened by bacteria into sec- ondary bile acids such as deoxycholic and lithocholic acid. The primary bile acids and their salts contain 24 carbon atoms and retain the ring structure of choles- terol from which they are formed (1-3).