細胞膜プレートを使用したサイトプローブ薬物の細胞膜透過性に関する基礎的検討

Drug efficacy depends on the amount of a preparation reaching the target tissue (grade of tissue transfer). In this experiment, we established the normal albumin concentration of a healthy adult (600 μ M) or a low-albumin state indicating marked liver hypofunction (100 μ M) on a cell membrane plate, and evaluated the cell membrane permeability of the probe agents. The cell membrane permeability of phenytoin or valproate depended on the concentration of albumin. Probe agent site-I and -II inhibitors, bucolome and oleic acid, respectively, increased the cell membrane permeability. In the future, the cell membrane permeability of probe agents should be further investigated to estimate the tissue transfer of agents based on various laboratory data (albumin, free fatty acids, uremic toxins, and bilirubin)

Basic study on flurbiprofen protein binding inhibition by an albumin site 2 binding inhibitor, 6-methoxy-2-naphthyl acetic acid.

非ステロイド性抗炎症薬(NSAID)フルルビプロフェン(FP)の蛋白結合率は約99%であり、組織移行性が低い。6-メトキシ-2-ナフチル酢酸(6MNA)は、NSAIDの1つであるナブメトンの活性代謝産物である。これらの薬物は、ともにヒト血清アルブミン(HSA)のサイトIIに強く結合する。私たちは、LLC-PK1を用いて6MNA添加時のFPの細胞膜透過性について調べた。この実験では、細胞膜プレートの上側を組織側、下側を血管側と想定した。下側のFPを含むHSA溶液に6MNAを添加後、上側、下側のFP濃度を測定した。上側へのFPの移行量は6MNAの添加により、Total FPおよびFree FP濃度ともに有意な増加を示した。下側の量は変化が見られなかった。臨床におけるナブメトンの併用はFPのようなサイトII結合性薬物の標的組織への移行量を増加させ、少量においても効果を高める可能性が示唆された。The protein binding rate of a nonsteroidal antiinflammatory drug (NSAID), flurbiprofen (FP), is about 99%, indicating its low tissue transfer. 6-Methoxy-2-naphthyl acetic acid (6MNA) is an active metabolite of an NSAID, nabumetone (Relifen ®). These drugs strongly bind to human serum albumin (HSA) site II, suggesting that protein binding inhibition by 6MNA may promote tissue transfer of FP. We investigated cell membrane permeability of FP in the presence of 6MNA using swine kidney cell line LLC-PK1, in which the upper and lower sides of the cell membrane plate (Transwell ®) were regarded as the tissue and vascular sides, respectively. After adding 6MNA to HSA solution containing FP on the lower side, the FP levels in the upper and lower solutions and cells were measured. FP transfer to the upper side was significantly promoted by the addition of 6MNA with regard to the total and free FP levels. No change in the FP level was noted in cells or wells. It was suggested that concomitant nabumetone may promote transfer of site II binding drugs, such as FP, to the target tissue, increasing the effect even at a low dose

Hepatic Arterial Infusion Therapy with Cisplatin using Protein Binding Inhibition : Pharmacokinetics and Antineoplastic Effects of Cisplatin Combined with L-Cysteine in Rats

Cisplatin の蛋白結合には共有結合が関与しており、L-cysteine はcisplatin の共有結合を低下させる。そこで、この蛋白結合阻害を利用してcisplatin の肝動注療法の応用性について検討を行った。実験では、Donryu系雄性ラットにおけるL-cysteine 併用時におけるcisplatin の体内動態と抗腫瘍効果の影響について検討した。その結果、L-cysteine 併用においてcisplatin のtotal とfree 濃度に有意な差はみられなかった。また肝癌ラットを使用したin vivo 実験系において、L-cysteine を併用したcisplatin の肝動注はcisplatin のみの投与に比べ、腫瘍増殖率が抑えられる傾向であることを示した。さらに肝組織中における腫瘍部と非腫瘍部におけるcisplatin 濃度において、L-cysteine 併用により腫瘍部と非腫瘍部に有意な差を認めることができた (p<0.01)。以上の結果より、L-cysteine の併用はcisplatin の肝動注療法へ応用できると考えられる。Covalent binding is involved in the protein binding of cisplatin. L-cysteine reduces the covalent binding of cisplatin. We investigated hepatic arterial infusion therapy with cisplatin using protein binding inhibition. In the present experiment, the pharmacokinetics and antineoplastic effects of cisplatin combined with L-cysteine in male Donryu rats were investigated. As a result, no significant difference was noted in the total and free concentrations of cisplatin combined with L-cysteine. In an in vivo experiment using rats with liver cancer, the hepatic arterial infusion of cisplatin combined with L-cysteine showed that it was the tendency that tumor growth rate was inhibited in comparison with administration only for cisplatin. In addition, concentrations of cisplatin increased significantly between tumor and non-tumor regions in liver tissue when combined with L-cysteine (p<0.01). Thus, L-cysteine can be combined with cisplatin for hepatic arterial infusion therapy

Seismic and Volcanic Activities in Southeast Asia

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