将可吸入微粒经肺部递送至小鼠后异烟肼和利福布汀的细胞内时间进程、药代动力学及生物分布
Intracellular time course, pharmacokinetics, and biodistribution of isoniazid and rifabutin following pulmonary delivery of inhalable microparticles to mice.
作者信息
Verma Rahul Kumar, Kaur Jatinder, Kumar Kaushlendra, Yadav Awadh Bihari, Misra Amit
机构信息
Pharmaceutics Division, Central Drug Research Institute, Chhattar Manzil Palace, Lucknow, India.
出版信息
Antimicrob Agents Chemother. 2008 Sep;52(9):3195-201. doi: 10.1128/AAC.00153-08. Epub 2008 Jun 30.
Intracellular concentrations of isoniazid and rifabutin resulting from administration of inhalable microparticles of these drugs to phorbol-differentiated THP-1 cells and the pharmacokinetics and biodistribution of these drugs upon inhalation of microparticles or intravenous administration of free drugs to mice were investigated. In cultured cells, both microparticles and dissolved drugs established peak concentrations of isoniazid ( approximately 1.4 and 1.1 microg/10(6) cells) and rifabutin ( approximately 2 microg/ml and approximately 1.4 microg/10(6) cells) within 10 min. Microparticles maintained the intracellular concentration of isoniazid for 24 h and rifabutin for 96 h, whereas dissolved drugs did not. The following pharmacokinetic parameters were calculated using WinNonlin from samples obtained after inhalation using an in-house apparatus (figures in parentheses refer to parameters obtained after intravenous administration of an equivalent amount, i.e., 100 microg of either drug, to parallel groups): isoniazid, serum half-life (t(1/2)) = 18.63 +/- 5.89 h (3.91 +/- 1.06 h), maximum concentration in serum (C(max)) = 2.37 +/- 0.23 microg x ml(-1) (3.24 +/- 0.57 microg x ml(-1)), area under the concentration-time curve from 0 to 24 h (AUC(0-24)) = 55.34 +/- 13.72 microg/ml(-1) h(-1) (16.64 +/- 1.80 microg/ml(-1) h(-1)), and clearance (CL) = 63.90 +/- 13.32 ml x h(-1) (4.43 +/- 1.85 ml x h(-1)); rifabutin, t(1/2) = 119.49 +/- 29.62 h (20.18 +/- 4.02 h), C(max) = 1.59 +/- 0.01 microg x ml(-1) (3.47 +/- 0.33 microg x ml(-1)), AUC(0-96) = 109.35 +/- 14.78 microg/ml(-1) h(-1) (90.82 +/- 7.46 microg/ml(-1) h(-1)), and CL = 11.68 +/- 7.00 ml x h(-1) (1.03 +/- 0.11 ml.h(-1)). Drug targeting to the lungs in general and alveolar macrophages in particular was observed. It was concluded that inhaled microparticles can reduce dose frequency and improve the pharmacologic index of the drug combination.
研究了将这些药物的可吸入微粒给予佛波酯分化的THP-1细胞后异烟肼和利福布汀的细胞内浓度，以及将微粒吸入或向小鼠静脉注射游离药物后这些药物的药代动力学和生物分布。在培养细胞中，微粒和溶解药物在10分钟内均建立了异烟肼（约1.4和1.1微克/10⁶细胞）和利福布汀（约2微克/毫升和约1.4微克/10⁶细胞）的峰值浓度。微粒使异烟肼的细胞内浓度维持24小时，利福布汀维持96小时，而溶解药物则不能。使用WinNonlin根据使用内部装置吸入后获得的样品计算了以下药代动力学参数（括号内的数字指对平行组静脉注射等量药物，即100微克任何一种药物后获得的参数）：异烟肼，血清半衰期（t₁/₂）=18.63±5.89小时（3.91±1.06小时），血清最大浓度（Cmax）=2.37±0.23微克·毫升⁻¹（3.24±0.57微克·毫升⁻¹），0至24小时浓度-时间曲线下面积（AUC₀-₂₄）=55.34±13.72微克/毫升⁻¹·小时⁻¹（16.64±1.80微克/毫升⁻¹·小时⁻¹），清除率（CL）=63.90±13.32毫升·小时⁻¹（4.43±1.85毫升·小时⁻¹）；利福布汀，t₁/₂=119.49±29.62小时（20.18±4.02小时），Cmax=1.59±0.01微克·毫升⁻¹（3.47±0.33微克·毫升⁻¹），AUC₀-₉₆=109.35±14.78微克/毫升⁻¹·小时⁻¹（90.82±7.46微克/毫升⁻¹·小时⁻¹），CL=11.68±7.00毫升·小时⁻¹（1.03±0.11毫升·小时⁻¹）。观察到药物一般靶向肺部，特别是肺泡巨噬细胞。得出的结论是，吸入微粒可以减少给药频率并改善药物组合的药理指数。
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