Disposition of naproxen, naproxen acyl glucuronide and its rearrangement isomers in the isolated perfused rat liver
Centre for Studies in Drug Disposition, The University of Queensland, Royal Brisbane Hospital, Australia.Xenobiotica (Impact Factor: 2.2). 07/2001; 31(6):309-19. DOI: 10.1080/00498250110052715
1. An isolated perfused rat liver (IPRL) preparation was used to investigate separately the disposition of the non-steroidal anti-inflammatory drug (NSAID) naproxen (NAP), its reactive acyl glucuronide metabolite (NAG) and a mixture of NAG rearrangement isomers (isoNAG), each at 30 microg NAP equivalents ml perfusate (n = 4 each group). 2. Following administration to the IPRL, NAP was eliminated slowly in a log-linear manner with an apparent elimination half-life (t 1/2) of 13.4 +/- 4.4h. No metabolites were detected in perfusate, while NAG was the only metablolite present in bile in measurable amounts (3.9 +/- 0.8% of the dose). Following their administration to the IPRL, both NAG and isoNAG were rapidly hydrolysed (t 1/2 in perfusate = 57 +/- 3 and 75 +/- 14 min respectively). NAG also rearranged to isoNAG in the perfusate. Both NAG and isoNAG were excreted intact in bile (24.6 and 14.8% of the NAG and isoNAG doses, respectively). 3. Covalent NAP-protein adducts in the liver increased as the dose changed from NAP to NAG to isoNAG (0.20 to 0.34 to 0.48% of the doses, respectively). Similarly, formation of covalent NAP-protein adducts in perfusate were greater in isoNAG-dosed perfusions. The comparative results suggest that isoNAG is a better substrate for adduct formation with liver proteins than NAG.
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ABSTRACT: Drug secretion into bile is typically considered a safe route of clearance. However, biliary delivery of some drugs or their reactive metabolites to the intestinal tract evokes adverse consequences due to direct toxic actions or indirect disruption of intestinal homeostasis. Biliary concentration of the chemotherapy agent 5-fluorodeoxyuridine (FUDR) and other compounds is associated with bile duct damage while enterohepatic cycling of antibiotics contributes to the disruptions of gut flora that produce diarrhea. The goal of this review is to describe key evidence that biliary delivery is an important factor in the intestinal injury caused by representative drugs. Emphasis will be given to 3 widely used drugs whose reactive metabolites are plausible causes of small intestinal injury, namely the nonsteroidal anti-inflammatory drug (NSAID) diclofenac, the immunosuppressant mycophenolic acid (MPA), and the chemotherapy agent irinotecan. Capsule endoscopy and other sensitive diagnostic techniques have documented a previously unappreciated, high prevalence of small intestinal injury among NSAID users. Clinical use of MPA and irinotecan is frequently associated such severe intestinal injury that dosage must be reduced. Observations from clinical and experimental studies have defined key events in the pathogenesis of these drugs, including roles for multidrug resistance-associated protein 2 (MRP2) and other transporters in biliary secretion and adduction of enterocyte proteins by reactive acyl glucuronide metabolites as a likely mechanism for intestinal injury. New strategies for minimizing the adverse intestinal consequences of irinotecan chemotherapy illustrate how basic information about key events in the biliary secretion of drugs and the nature of their proximate toxicants can lead to safer protocols for drugs.Pharmacology [?] Therapeutics 01/2007; 112(3):649-67. DOI:10.1016/j.pharmthera.2006.05.007 · 9.72 Impact Factor
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ABSTRACT: This paper aims to provide a scientifically based perspective on issues surrounding the proposed toxicology testing of synthetic drug metabolites as a means of ensuring adequate nonclinical safety evaluation of drug candidates that generate metabolites considered either to be unique to humans or are present at much higher levels in humans than in preclinical species. We put forward a number of theoretical considerations and present several specific examples where the kinetic behavior of a preformed metabolite given to animals or humans differs from that of the corresponding metabolite generated endogenously from its parent. The potential ramifications of this phenomenon are that the results of toxicity testing of the preformed metabolite may be misleading and fail to characterize the true toxicological contribution of the metabolite when formed from the parent. It is anticipated that such complications would be evident in situations where (a) differences exist in the accumulation of the preformed versus generated metabolites in specific tissues, and (b) the metabolite undergoes sequential metabolism to a downstream product that is toxic, leading to differences in tissue-specific toxicity. Owing to the complex nature of this subject, there is a need to treat drug metabolite issues in safety assessment on a case-by-case basis, in which a knowledge of metabolite kinetics is employed to validate experimental paradigms that entail administration of preformed metabolites to animal models.Toxicology and Applied Pharmacology 01/2007; 217(2):143-52. DOI:10.1016/j.taap.2006.08.009 · 3.71 Impact Factor
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ABSTRACT: Naproxen sodium (NAS) is a non-steroidal anti-inflammatory drug commonly used for the reduction of moderate to severe aches and pains. This study presents a simple and sensitive high-performance liquid chromatographic method for the determination of in-vitro solubility of NAS. Chromatographic separation of NAS was achieved on a reversed-phase column (Waters Spherisorb S10 ODS2 C18 200x4.6 mm column) with the mobile phase consisted of 0.05M phosphate buffer (pH 4.0), methanol and acetonitrile (50:20:30 v/v), at a flow rate 1 mL.min-1. Chromatographic detection of NAS was performed at 230 nm with UV detector system. The retention time was about 7 min. Calibration curve was linear over the concentration range of 5-150 μg.mL-1. The limit of quantitation was found to be 78 ng.mL-1. The intra- and inter-day precision relative standard deviation was 3.7% or less, and the accuracy was within 5.4% deviation of the nominal concentration. The proposed HPLC method was successfully applied to the analysis of NAS solubility.Hacettepe University Journal of the Faculty of Pharmacy 01/2008; 28(1):49-62.
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