In vivo effects of cyclosporin A and ketoconazole on the pharmacokinetics of representative substrates for P-glycoprotein and cytochrome P450 (CYP) 3A in rats
In vivo effects of cyclosporin A and ketoconazole on the pharmacokinetics of representative substrates for P-glycoprotein and cytochrome P450 (CYP) 3A in rats
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DOI：
10.1248/bpb.28.316
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发表时间：
2005-02-01
影响因子：
2
通讯作者：
Takada, K
中科院分区：
文献类型：
--
作者：
Kageyama, M;Namiki, H;Takada, K
本文研究了P-糖蛋白（Pgp）和细胞色素P450（CYP）3A抑制剂环孢素A（CsA）和酮康唑（KCZ）在大鼠体内对罗丹明123（Rho 123）、奈非那韦（NFV）和红霉素（EM）药代动力学的影响。CsA或KCZ（静脉给药后0-20 mg/kg）静脉预处理后，已知Pgp底物Rho 123的胆汁排泄清除率（Cl-胆汁）分别最大降低85.6%或54.1%，表明KCZ在肝脏中的抑制效力约为Pgp的一半。未经CsA或KCZ预处理时，Cl-胆汁的清除率相对于Rho 123、NFV和EM的总清除率分别为10.5%、0.07%和31.1%。CsA预处理后，NFV和EM的清除率显著降低，且与CsA剂量呈依赖关系; CZ预处理后，NFV和EM的清除率显著升高，且与KCZ剂量呈依赖关系。而在肝脏中，Pgp对Rho 123、NFV和EM静脉给药后药代动力学参数变化的贡献远小于CYP 3A。门静脉Rho 123和EM，但不NFV后，在10妈妈CsA的存在下，在空肠袢内给药水平显着增加，而在25妈妈KCZ的存在下，在空肠袢，这些基板的门静脉水平相比，对照水平没有显着变化。结论：KCZ对CYP 3A和Pgp具有双重抑制作用，对Pgp的抑制作用约为CsA的一半。此外，通过CYP 3A的代谢对这些底物的清除贡献更大，而这些底物通过肝脏中的Pgp排泄。在小肠中，Pgp的贡献是决定EM口服生物利用度的一个比通过β-内酰胺酶代谢更重要的因素。NFV的消除主要依赖于通过CYP 3A的肝脏代谢，肝脏和肠道中的Pgp外排机制对体内条件下NFV的口服生物利用度没有重要贡献，尽管已证明NFV在体外条件下是Pgp的底物。
In this study, the in vivo effects of cyclosporin A (CsA) and ketoconazole (KCZ), which are used as inhibitors of P-glycoprotein (Pgp) and cytochrome P450 (CYP) 3A, respectively, on the pharmacokinetics of rhodamine 123 (Rho123), nelfinavir (NFV) and erythromycin (EM) were evaluated in rats. The biliary excretion clearance (Cl-bile) of a known Pgp substrate, Rho123, after intravenous pretreatment with CsA or KCZ (0-20 mg/kg after i.v. administration) showed maximum reduction by 85.6 or 54.1%, respectively, suggesting that the inhibitory potency of KCZ is about half that of Pgp in the liver. Without pretreatment with CsA or KCZ, the clearance ratio of Cl-bile relative to the total body clearances of Rho123, NFV and EM was 10.5, 0.07 and 31.1%, respectively. After CsA pretreatment, these ratios decreased markedly in a manner dependent on the dose of CsA, while after CZ pretreatment the clearance ratios of NFV and EM increased significantly in a manner dependent on the dose of KCZ. However, in the liver, the contribution of Pgp to the changes in the pharmacokinetic parameters of Rho123, NFV and EM after intravenous administration was much less than that of CYP3A. The portal levels of Rho123 and EM but not NFV after intra-loop administration in the presence of 10 mum CsA in the jejunal loop increased significantly, while in the presence of 25 mum KCZ in the jejunal loop, the portal levels of those substrates showed no notable change as compared to the control levels. In conclusion, KCZ had dual potency to inhibit CYP3A and Pgp, and its inhibitory potency for Pgp was half that of CsA in the rat liver. In addition, metabolism via CYP3A contributed more significantly to the clearance of these substrates that did excretion via Pgp in the liver. In the small intestine, the contribution of Pgp is a more important factor in determining the oral bioavailability of EM than metabolism via CYP enzymes. The elimination of NFV is mainly dependent on liver metabolism via CYP3A, and the Pgp efflux mechanism in the liver and intestine did not contribute as importantly to the oral bioavailability of NFV under in vivo conditions, although NFV has been demonstrated to be a substrate of Pgp under in vitro conditions.