A Practical Approach, Second Edition=Ronald D. Ho.pdf

USE OF TOXICOKINETICS IN DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY 579CC maxDistributionAbsorptionAUCEliminationDoset maxTimeFigure 13.2Typical blood plasma drug concentration vs. time curve following a single oral dose, depictingthe maximum plasma drug concentration (C max ) achieved at time t max . Shading indicates the areaunder the concentration vs. time curve (AUC).C max and AUC can be determined graphically or computationally, with the AUC calculated asthe sum area of trapezoids defined by the sampling time points on the horizontal axis. C max indicatesthe highest systemic concentration achieved, whereas the AUC gives an indication of the totalityof systemic exposure. Depending upon route of administration and the rates of absorption, distribution,and elimination, a wide variety of blood plasma concentration vs. time profiles may beobserved. As will be discussed subsequently, a key application of toxicokinetics is to identify theexposure metric (e.g., C max , C ss , or AUC) that best correlates with toxicity potential. Experimentally,different routes of administration can be used to produce profiles having comparable AUC whileC max is significantly different, or vice versa (Figure 13.3).The net rate of compound elimination from the central compartment (blood plasma in theseexamples) is calculated from the semilogarithmic plot of compound concentration vs. time (Figure13.4). If such a plot is linear, the data are well described by the one-compartment model, and theslope of the resulting straight line gives the elimination rate constant (k el ) in the reciprocal unit oftime (e.g., min –1 or h –1 ):k el = 2.303 × slope (13.2)Another useful pharmacokinetic parameter is the apparent elimination half-life (t ½ ), the timefor the compound concentration in the central compartment to decrease by one-half, which can bedetermined graphically (Figure 13.4) or computationally. The units of half-life are time (e.g., minor h). In a one compartment model:t ½ = 0.693 / k el (13.3)Typically in a two-compartment model, the terminal elimination half-life (t ½ ) is quoted. Moreprecisely, there are two composite rate constants (k α and k β ) reflecting distribution (k 12 and k 21 ) andelimination (k el ). These can be used to calculate t ½α and t ½β , respectively, and one can compute an“effective” half-life for the central compartment from the AUC-weighted average of t ½α and t ½β ,i.e., effective half-life = (t ½α )(fAUC α ) + (t ½β )(fAUC β ), where fAUC α and fAUC β represent thefraction of the total AUC marked by lines α and β, respectively (see Figure 13.4).© 2006 by Taylor & Francis Group, LLC