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首页> 外文期刊>薬物動態 >Comparative analysis of in vitro and in vivo pharmacokinetic parameters related to individual variability of GTS-21 in canine
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Comparative analysis of in vitro and in vivo pharmacokinetic parameters related to individual variability of GTS-21 in canine

机译：与犬类GTS-21个体变异性有关的体外和体内药代动力学参数的比较分析

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To clarify the cause of the anine individual variability in plasma concentration after oral adminsitration of GTS-21,we evaluated in vitro the metabolismto 4-OH-GTS-21 in liver microsomes of the same individuals from in vivo pharmacokinetic study.First,we applied to the Michaelis-Menten kinetic parameters to a dispersion model,and compared hepatic availability (F_H) and hepatic clearance (CL_H) values from in vitro with bioavailability(F),hepatic plasma flow (Q_(PH),and plsma clearance (CL_P) values from in vivo.The ratios of CL_H to Q_(PH) were ranged 0.74 to 0.94,suggesting that GTS-21 is a hepatic plasma flow-limiting drug.A significant correlation of F_H and F in the four dogs (r=0.995,p=0.005) indicates that the variability is predominatly caused by GTS-21 O4-demethylase activity.Second,we specified the cytochrome P450 (CYP) enzymes that are involved with the metabolism by chemcial inhibition.#alpha#-Naphthoflavone,furafylline,quinidine,quinine,and troleandomycin significanlty inhibited GTS-21 O4-demethylase activity.Thus CYP1A,CYP2D15,and CYP3A12 were involved with O4-demethylation.The variability in controlactivity decreased on addition of #alpha#-naphthoflavone and furafylline.Third,we quantified the contents of CYP1A and CYP3A12 by enzyme-linked immunosorbent assay.The content of CYP1A was consistentwith GTS-21 O4-demethylase activity.We concluded that canine liver CYP1A causes the individual variability in GTS-21 plasma concentration after oral administration.
机译：为了阐明GTS-21口服置置血浆浓度的血浆浓度的原因，我们在体内药代动力学研究中在同一个体的肝脏微粒体中评估了在体外的代谢4-OH-GTS-21。首先，我们申请了到分散模型的Michaelis-Menten动力学参数，并比较肝可用性（F_H）和肝脏间隙（CL_H）值，其具有生物利用度（F），肝等离子体流动（Q_（pH）和PLSMA间隙（CL_P）在体内的值。Cl_H至Q_（pH）的比率范围为0.74至0.94，表明GTS-21是肝脏血浆流量限制药物。F_H和F的显着相关性（r = 0.995， P = 0.005）表明可变性主要由GTS-21 O 4脱甲基化酶活性引起。二酮，我们指定了通过化学抑制涉及代谢的细胞色素P450（CYP）酶。＃alpha＃-Naphthoflavone，Furafylline，奎尼丁，奎宁和特罗灵霉素意义inh Ibited GTS-21 O4-脱甲基酶活性。CYP1A，CYP2D15和CYP3A12涉及O4-去甲基化。添加剂的控制活性的可变性降低了#α-萘洛伐克和Furafylline。第三，我们量化了CYP1A和CYP3A12的内容酶联免疫测定。CYP1a的含量是GTS-21 O 4脱甲基酶活性的。我们得出结论，犬肝CYP1A在口服给药后导致GTS-21等离子体浓度的个体变异性。

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