imatinib metabolism and disposition in isolated rat perfused liver

Authors

shiva moghtadaee

biopharmaceutics and pharmacokinetics division, department of pharmaceutics, faculty of pharmacy, tehran university of medical sciences,tehran, iran yalda hossein-zade ardakani

biopharmaceutics and pharmacokinetics division, department of pharmaceutics, faculty of pharmacy, tehran university of medical sciences,tehran, iran hoda lavasani

biopharmaceutics and pharmacokinetics division, department of pharmaceutics, faculty of pharmacy, tehran university of medical sciences,tehran, iran mohammadreza rouini

biopharmaceutics and pharmacokinetics division, department of pharmaceutics, faculty of pharmacy, tehran university of medical sciences,tehran, iran

abstract

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.

Upgrade to premium to download articles

Sign up to access the full text

Already have an account?login

similar resources

Imatinib metabolism and disposition in isolated rat perfused liver

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 ima...

full text

Xylitol metabolism in the isolated perfused rat liver.

1. Loading the isolated perfused liver from well-fed rats with xylitol (20mm) caused a depletion of adenine nucleotides and P(i) and an accumulation of alpha-glycerophosphate. The ATP content fell to 66% of the control value after 10min and to 32% after 80min. The ADP and AMP contents also fell. After 80min 63% of the total adenine nucleotides and 59% of the P(i) had been lost. 2. The alpha-gly...

full text

Phthalate ester metabolism in the isolated, perfused rat liver system.

A series of experiments, performed at Johns Hopkins University, which led to our finding that plasticizers are extracted from poly-(vinyl chloride) (PVC) plastic by blood and biologic fluids will be described. The experiments began with the appearance of an unknown compound in the isolated perfused liver system. Livers were perfused with a mixture of synthetic plasma containing bovine serum alb...

full text

The isolated perfused rat liver.

The disposition of mefloquine has been investigated in the isolated perfused rat liver (IPRL) preparation after the administration of [C]mefloquine HCI (3.8 mg, 4 1 Ci, quinoline ring labeled). Mefloquine underwent avid hepatic uptake within 10 min of dosing. Also at this point, hepatic oxygen consumption was reduced markedly in four of the six IPRL preparations, but was restored completely by ...

full text

Disposition and covalent binding of diflunisal and diflunisal acyl glucuronide in the isolated perfused rat liver.

Acyl glucuronides are intrinsically reactive metabolites of carboxylate drugs, capable of undergoing hydrolysis, intramolecular rearrangement (isomerization via acyl migration), and intermolecular transacylation reactions. Transacylation with nucleophilic groups located on protein molecules leads to covalent drug-protein adducts. Protein adducts can also form from the rearrangement isomers via ...

full text

My Resources

Save resource for easier access later


Journal title:
iranian journal of pharmaceutical sciences

جلد ۱۲، شماره ۱، صفحات ۶۹-۸۴

Hosted on Doprax cloud platform doprax.com

copyright © 2015-2023