泊沙康唑预防和治疗侵袭性真菌病精要课件.ppt

* * 主要作用方式：抑制真菌麦角甾醇的生物合成（依赖于细胞色素P450酶，羊毛甾醇 14?-去甲基化酶[CYP51A1]) 侧链延长，可能会使药物与受体位点结合更加紧密和稳定 * 曲霉菌丝与上皮细胞接触后，泊沙康唑迅速从上皮细胞转移到孢子的细胞膜，未经过吞噬等过程 * * This slide shows posaconazole distribution at steady-state in plasma and pulmonary (bronchoalveolar lavage) components. The study included 25 healthy volunteers who received 14 doses of posaconazole oral suspension (400mg twice daily) with a high-fat meal over 8 days.（25 subjects enrolled in the study, 21 completed BAL.） Steady-state levels of posaconazole were approximately 33-fold higher in alveolar cells than in plasma, and did not decline in the 24 hours after the last dose However, posaconazole levels were substantially higher than the MIC90 for Aspergillus spp. in all 3 compartments (plasma, epithelial lining fluid and alveolar cells), indicating that the drug should be active against this pathogen. Reference Conte JE, Golden JA, Krishna G et al. Intrapulmonary pharmacokinetics and pharmacodynamics of posaconazole at steady state in healthy subjects. Antimicrob Agents Chemother. 2009;53:703. * * * 伊曲康唑 CYP2C9 inhibitor ？ * * The CYP3A4 isoenzyme accounts for 29% of human hepatic and 70% of gastrointestinal tract CYP activity. of the three isoenzymes that are associated with azole-related drug interactions, 泊沙康唑conazole interacts only with CYP3A4 and only as a CYP3A4 inhibitor. * Posaconazole has a reduced potential for drug interactions compared with other azole antifungals because it inhibits only the cytochrome P450 (CYP) enzyme 3A4.1 The contraindications are similar to those for other azoles that inhibit CYP3A4, and caution is advised during coadministration of CYP3A4 substrates administered intravenously or orally.2 The dose of the CYP3A4 substrate may need to be reduced (eg, ciclosporin and tacrolimus). The effect of posaconazole on plasma concentrations of orally administered CYP3A4 substrates is not known, but a much larger effect than that observed for intravenously administered substrates could be expected.