هدی لواسانی

Alteration in drug metabolism is very likely in diabetes mellitus. This study assessed changes in CYP2C19 enzymatic activity in the liver using omeprazole as a probe in the animal model of type II diabetes (T2DM) before and after treatment with metformin and cinnamon. Twenty-eight male Wistar rats were randomly divided into seven groups. Fourteen days after induction of type 2 diabetic mellitus (T2DM), rats in the test group received metformin, cinnamon, and metformin plus cinnamon daily for 14 days. On day 28, rats were subjected to liver perfusion by Krebs-Henseleit buffer containing omeprazole as a CYP2C19 probe. Perfusate samples were analyzed by HPLC-UV to evaluate the activity of CYP2C19. Mean metabolic ratio of omeprazole was changed from 0.091±0.005 in the control group to 0.054±0.005 in the untreated-diabetic rats. This average was increased inordinately to 0.218±0.036 in the treated rats with metformin. Interestingly, the administration of cinnamon in combination with metformin in diabetic rats caused the enzyme activity to return to (0.085±0.002) approximately the observed levels in the control group (0.091±0.005). Results showed that despite the suppression of the CYP2C19 enzyme activity in T2DM rats, metformin treatment could increase the enzyme activity. Simultaneous application of cinnamon and metformin can modulate the function of CYP2C19 to the observed level in the control group and make it more predictable to treat diabetes mellitus and fate of drugs that are metabolized by this enzyme.

Imatinib is an orally administered tyrosine kinase inhibitor which inhibits the Bcr-Abl protein-tyrosine kinase with high selectivity. Imatinib is rapidly absorbed from the gut, after oral intake and has an almost absolute bioavailability of 98%. The metabolism of imatinib is mediated by the cytochrome P450 (CYP) isoenzymes in the liver and gut wall. CGP74588 is a major active metabolite of imatinib. The study was performed on Male Sprague-Dawley rats (250-300 g) housing under artificial light on a 12-h light/dark cycle with free access to standard laboratory chow and water. Re-circulating (at imatinib concentration of 1 and 5 µg/ml) and single-pass (imatinib dose of 1mg) perfusion modes in the presence and absence of BSA were tested. Throughout the experiment, perfusate temperature (37±0.5 C°), pH (7.4±0.2) and liver viability (ALT and AST) were monitored. The concentrations of imatinib and its main metabolite in perfusion buffer and liver homogenate were determined by a validated HPLC method. No metabolite was detected in outlet perfusate in all conditions. However negligible amounts of metabolite were found in liver homogenate at 1 and 5 µg/ml imatinib concentrations in re-circulating perfusion mode. The rapid and remarkable disappearance of imatinib from perfusate was related to its accumulation in liver. Statistical moment definition was used to calculate some pharmacokinetic parameters. These calculations also confirmed liver accumulation and slow and sustained dissociation of imatinib from liver.