Berezhkovskiy Leonid M
Roche Palo Alto, California 94304, USA.
J Pharm Sci. 2006 Apr;95(4):834-48. doi: 10.1002/jps.20570.
A common calculation of oral bioavailability is based on the comparison of the areas under the concentration-time curves after intravenous and oral drug administration. It does not take into account that after the oral dosing a drug enters the systemic circulation in different states, that is, as free fraction, protein bound and partitioned into blood cells, and plasma lipids, while after intravenous input it is introduced into the systemic circulation only as a free fraction. Consideration of this difference leads to a novel equation for the oral bioavailability. In general, the traditional calculation overestimates the oral bioavailability. For a widely applied model of a linear pharmacokinetic system with central (plasma) drug elimination it is shown that the traditional calculation of the oral bioavailability could substantially overestimate the true value. If the existence of an immediate equilibrium between different drug fractions in blood is assumed, the obtained equation becomes identical to the traditional one. Thus the deviation of oral bioavailability from the value given by a common calculation appears to be a kinetic phenomenon. The difference could be significant for the drugs with the rate constant of elimination from plasma of the same order of magnitude or greater than the dissociation rate constant of drug-protein complexes, or the off-rate constant of partitioning from the blood cells, if the blood concentration profiles were used to calculate the oral bioavailability.
口服生物利用度的一种常见计算方法是基于静脉注射和口服给药后浓度-时间曲线下面积的比较。它没有考虑到口服给药后药物以不同状态进入体循环，即作为游离部分、与蛋白质结合并分配到血细胞和血浆脂质中，而静脉注射后它仅作为游离部分引入体循环。考虑到这种差异会得出一个关于口服生物利用度的新方程。一般来说，传统计算会高估口服生物利用度。对于具有中心（血浆）药物消除的线性药代动力学系统的广泛应用模型，结果表明口服生物利用度的传统计算可能会大幅高估真实值。如果假设血液中不同药物部分之间存在即时平衡，那么得到的方程就与传统方程相同。因此，口服生物利用度与常规计算值的偏差似乎是一种动力学现象。如果使用血药浓度曲线来计算口服生物利用度，对于那些从血浆中消除的速率常数与药物-蛋白质复合物的解离速率常数或从血细胞中分配的解离速率常数处于同一数量级或更大的药物，这种差异可能会很显著。
