کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2484830 1114338 2013 16 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Application of permeability-limited physiologically-based pharmacokinetic models: Part I–digoxin pharmacokinetics incorporating P-glycoprotein-mediated efflux
موضوعات مرتبط
علوم پزشکی و سلامت داروسازی، سم شناسی و علوم دارویی اکتشاف دارویی
پیش نمایش صفحه اول مقاله
Application of permeability-limited physiologically-based pharmacokinetic models: Part I–digoxin pharmacokinetics incorporating P-glycoprotein-mediated efflux
چکیده انگلیسی

A prerequisite for the prediction of the magnitude of P-glycoprotein (P-gp)-mediated drug–drug interactions between digoxin and P-gp inhibitors (e.g. verapamil and its metabolite norverapamil) or P-gp inducers (e.g. rifampicin) is a predictive pharmacokinetic model for digoxin itself. Thus, relevant in vitro metabolic, transporter and inhibitory data incorporated into permeability-limited models, such as the “advanced dissolution, absorption and metabolism” (ADAM) module and the permeability-limited liver (PerL) module, integrated with a mechanistic physiologically-based pharmacokinetic (PBPK) model such as that of the Simcyp Simulator (version 12.2) are necessary. Simulated concentration–time profiles of digoxin generated using the developed model were consistent with observed data across 31 independent studies [13 intravenous single dose (SD), 12 per oral SD and six multiple dose studies]. The fact that predicted tmax (time of maximum plasma concentration observed) and Cmax (maximum plasma concentration observed) of oral digoxin were similar to observed values indicated that the relative contributions of permeation and P-gp-mediated efflux in the model were appropriate. There was no indication of departure from dose proportionality over the dose range studied (0.25–1.5 mg). All dose normalised area under the plasma concentration-time curve profiles (AUCs) for the 0.25, 0.5, 0.75 and 1 mg doses resembled each other. Thus, PBPK modelling in conjunction with mechanistic absorption and distribution models and reliable in vitro transporter data can be used to assess the impact of dose on P-gp-mediated efflux (or otherwise).

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 102, Issue 9, September 2013, Pages 3145–3160
نویسندگان
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