Toxicokinetic of Carbamazepine in Diabetic Rats

E Ezzeldin1,2. 1Drug Bioavailability Center, National Organization for Drug Control and Research, P.O.Box 29 Cairo, Egypt, 2Drug Bioavailability Laboratory, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia

Abstract

Background. Epilepsy is one of the world’s most prevalent non-communicable diseases affecting approximately 25 million people in the world (Theodore, 2001). Carbamazepine (CBZ) is one of the most widely used antiepileptic drugs. It is classified as a narrow therapeutic index drug (Johannessen and Landmark, 2010) and is belonging to a group of drugs that are highly susceptible to interactions. Diabetes mellitus is spread throughout the world (Diabetes Atlas News, 2011). Population-based studies of drug utilization demonstrate that 19-24 % of patients with epilepsy suffer from other diseases including diabetes (Tsiropoulos et al., 2006).

Objective. The aim of the present work is to study the effects of diabetes on the pharmacokinetics and pharmacodynamics of carbamazepine, as a narrow therapeutic index drug, in rats.

Methods. Diabetes was induced in adult male Sprague Dawley rats by streptozotocin (60 mg/kg, ip) (Wang et al., 2008). Animals were divided into two sets, normal and diabetic sets; each set was divided into control and two-treated groups, 10 animals each, Rats received carbamazepine orally in dose levels of 100 and 200 mg/kg (Shannon et a., 2008) once daily for 28 days. Carbamazepine plasma levels were determined by a validated HPLC method. The pharmacokinetic profiles were carried out over a period of 24 hours. The liver functions were evaluated by the determination of, alkaline phosphatise, albumin (Doumas et al., 1971), ALT and AST plasma levels (Reitman and Frankel, 1957, Kidney functions were determined by plasma creatinine and urea concentrations (Patton and Crouch, (1977). Histopathology of rats' livers and kidneys were also investigated.

Results. Diabetes itself showed a significant increase in serum levels of AST, ALT, alkaline phosphatase, urea, and creatinine by 11.9%, 3.5%, 33.14%, 141.0% and 124.28%, respectively in comparison to normal rats (P>0.05). The obtained results also showed that Liver enzymes, urea and creatinine levels were significantly elevated in carbamazepine-treated groups (P<0.05). These effects were more pronounced in diabetic rats. These changes are compatible with results obtained from liver and kidney histopathological investigations. Diabetes significantly altered the rate and extent of carbamazepine absorption (P<0.05). Carbamazepine pharmacokinetic parameters showed that diabetes reduced Cmax, AUC0-24 and AUC0-inf by 6.8%, 13.6 % and 22.8%, respectively following administration of carbamazepine 100 mg/kg and by 20.3%, 12.2% and 32.8%, respectively following administration of carbamazepine 200 mg/kg.

Conclusion. Diabetes potentiated carbamazepine toxicity in rats which marked by alterations in liver and kidney functions as well as the changes observed in their histopathological examinations. In addition,diabetes inhibited the rate and extent of carbamazepine absorption. These results reflect that the increases of carbamazepine toxicity by diabetes may be related to the pharmacodynamic effects rather than pharmacokinetic effects. Carbamazepine pharmacokinetic changes induced by diabetes should be clinically stressed as carbamazepine is a drug with narrow therapeutic index.