Biol Pharm Bull. 1998 Dec;21(12):1344-7.
Quinone-dependent tertiary amine N-oxide reduction in rat blood.

Kitamura S, Terada A, Inoue N, Kamio H, Ohta S, Tatsumi K.

Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Japan.

Rat blood exhibited a significant quinone-dependent N-oxide reductase activity towards imipramine N-oxide. The reduction mediated by the blood proceeded in the presence of both NAD(P)H and menadione under anaerobic conditions. When menadione was replaced with 1,4-naphthoquinone or 9,10-phenanthrenequinone, similar results were obtained. The reduction was also mediated by the combination of rat erythrocytes and plasma. The reducing activity was inhibited by dicumarol and carbon monoxide. When boiled plasma was combined with untreated erythrocytes, the N-oxide reducing activity was abolished. In contrast, when boiled erythrocytes were combined with untreated plasma, the activity was unchanged. These results suggest that the activity is caused by the heme of hemoglobin in erythrocytes and quinone reductase in plasma. In fact, erythrocytes and hemoglobin have the ability to reduce the N-oxide when supplemented with DT-diaphorase purified from rat liver in the presence of both NAD(P)H and menadione. Hemoglobin also exhibits N-oxide reductase activity with reduced menadione (menadiol). Furthermore, hematin exhibits a significant reducing activity in the presence of menadiol. The reduction appears to proceed in two steps. The first step is enzymatic reduction of quinones to dihydroquinones by quinone reductase(s) with NADPH or NADH in plasma. The second step is nonenzymatic reduction of imipramine N-oxide to imipramine by the dihydroquinones, catalyzed by the heme group of hemoglobin in erythrocytes. Cyclobenzaprine [Flexeril] N-oxide and brucine N-oxide are similarly transformed to the corresponding amines by the above reducing system in blood. These results suggest that blood plays an important role in the reduction of tertiary amine N-oxides to tertiary amines.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9881651&dopt=Abstract cyclobenzaprine Flexeril





Drug Metab Dispos. 1999 Jan;27(1):92-7.
A unique tertiary amine N-oxide reduction system composed of quinone reductase and heme in rat liver preparations.

Kitamura S, Sugihara K, Tatsumi K.

Institute of Pharmaceutical Science, Hiroshima University School of Medicine, Kasumi 1-2-3, Minami-ku, Hiroshima 734-8551, Japan.

The results of this study show the quinone-dependent reduction of tertiary amine N-oxides to the corresponding tertiary amines by rat liver preparations. The reduction of imipramine N-oxide to imipramine mediated by liver mitochondria, microsomes, and cytosol proceeded in the presence of both NAD(P)H and menadione under anaerobic conditions. When menadione was replaced with 1, 4-naphthoquinone or 9,10-anthraquinone, similar results were obtained in the cytosolic reduction. The quinone-dependent reducing activity in liver cytosol was inhibited by dicumarol and carbon monoxide. This result suggested that the activity is caused by DT-diaphorase, a cytosolic quinone reductase, and hemoproteins in liver cytosol. In fact, catalase and hemoglobin showed the ability to reduce imipramine N-oxide when supplemented with DT-diaphorase. The hemoproteins also exhibited the N-oxide reductase activity with reduced menadione, menadiol. The N-oxide reductase activity of the hemoproteins was also exhibited with 1,4-dihydroxynaphthalene, 1,4,9, 10-tetrahydroxyanthracene, or 1,4-dihydroxy-9,10-anthraquinone. Furthermore, hematin revealed a significant N-oxide-reducing activity in the presence of menadiol. The reduction appears to proceed in two steps. The first step is reduction of menadione to menadiol by a quinone reductase with NADPH or NADH. The second step is nonenzymatic reduction of tertiary amine N-oxides to tertiary amines by menadiol, catalyzed by the heme group of hemoproteins. Cyclobenzaprine [Flexeril] N-oxide and brucine N-oxide were also transformed similarly to the corresponding amine by the quinone-dependent reducing system.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9884315&dopt=Abstract cyclobenzaprine Flexeril


spcorp.com

Oral osmotic delivery systems containing polyethylene oxide (PEO, a water-swellable polymer) were designed and the release of cyclobenzaprine hydrochloride (model drug) from the devices was investigated. The systems consisted of model drug, mannitol (osmotic agent), and increasing amounts of PEO surrounded by a semipermeable membrane drilled with a delivery orifice. There was a decrease in drug release rate with PEO in the core. This may be due to solubility-modulating properties of the polymer. Visual inspection of the devices with PEO showed significant swelling during dissolution testing. Swelling (internal pressure) may influence water inhibition rate into the core and subsequently drug release rate. The release rates were a function of membrane thickness. The release rates were independent of orifice size (range of 150-510 microns diameter) and hydrodynamic conditions for the devices. This would be advantageous in the delivery of drugs in man.

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spcorp.com

Osmotically rupturable systems were developed and the release of cyclobenzaprine hydrochloride (model drug) from the systems was investigated. Systems were designed using mannitol (osmotic agent) and increasing amounts of polyethylene oxide (PEO, a water-swellable polymer) surrounded by a semipermeable membrane. When placed in an aqueous environment, osmotic water imbibition into the systems distended and swelled the systems until the membrane ruptured and released the active compound to the outside environment. Tablets with increasing amount of PEO exhibited longer rupture times. This may be due to osmotic pressure-modulating properties of the polymer, changing the rate of water imbibition into the systems. The integrity of the membranes was investigated using high-pressure mercury intrusion porosimetry. Minimal mercury intrusion into the membrane structure and core tablet indicated membrane integrity and lack of defective areas or pin-holes. The results were in agreement with the release profiles where no drug release was detected prior to membrane rupture. Mercury intrusion porosimetry appears to be a promising technique for evaluation of membrane integrity. Once the systems ruptured, drug was released by osmotic pumping and diffusion mechanisms through the ruptured area. There was a decrease in drug release rate with inclusion of PEO in the core. The effects of film thickness on rupture and release times were also investigated. Devices with thicker films produced longer rupture times. This is in agreement with the theoretical prediction.

Online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12149962&dopt=Abstract cyclobenzaprine Flexeril