Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
Pharm Res. 2010 Jul;27(7):1237-54. doi: 10.1007/s11095-010-0049-2. Epub 2010 Apr 6.
To obtain mathematical solutions that correlate drug and metabolite exposure and systemic bioavailability (F (sys)) with physiological determinants, transporters and enzymes.
A series of physiologically-based pharmacokinetic (PBPK) models that included renal excretion and sequential metabolism within the intestine and/or liver as metabolite formation organs were developed. The area under the curve for drug (AUC) and formed metabolite (AUC{mi,P}) were solved by matrix inversion.
The PBPK models revealed that AUC{mi,P} was dependent on dispositional parameters (transport and elimination) for the drug and metabolite. The solution was unique for each metabolite formation organ and was dependent on the type of drug and metabolite elimination organs. The AUC ratio of the formed metabolite after oral and intravenous drug dosing was useful for determination of the fraction absorbed (F (abs)) and not the systemic bioavailability (F (sys)) when either intestine or liver was the only drug elimination organ.
The AUC ratio of the formed metabolite after oral and intravenous drug dosing differed from that for drug and would not provide F (sys). However, the AUC ratio of the formed metabolite for oral and intravenous drug dosing furnished the estimate of F (abs) when intestine or liver was the only drug metabolic organ.
获得与生理决定因素、转运体和酶相关的药物和代谢物暴露量和全身生物利用度（F(sys)）的数学解。
开发了一系列包含肾脏排泄和在肠道和/或肝脏中作为代谢物形成器官的顺序代谢的基于生理学的药代动力学（PBPK）模型。通过矩阵反演求解药物（AUC）和形成的代谢物（AUC{mi,P}）的曲线下面积。
PBPK 模型表明，AUC{mi,P}取决于药物和代谢物的处置参数（转运和消除）。该解对于每个代谢物形成器官都是唯一的，并且取决于药物和代谢物消除器官的类型。口服和静脉给药后形成的代谢物的 AUC 比值可用于确定吸收分数（F(abs)），而不是当肠道或肝脏是唯一的药物消除器官时系统生物利用度（F(sys)）。
口服和静脉给药后形成的代谢物的 AUC 比值与药物不同，不会提供 F(sys)。然而，当肠道或肝脏是唯一的药物代谢器官时，口服和静脉给药后形成的代谢物的 AUC 比值可提供 F(abs)的估计值。
