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Journal of Pharmacokinetics and Biopharmaceutics, Vol. 2, No. 6, 1974
Application of the Wagner-Nelson AbsorptionMethod to the Two-Compartment Open Model
John G. Wagner !,2
Received Jan. 24, 1974~Final July 22, 1974
This report considers the application of the W'agner-Nelson method to both one- and two-compart-ment open model data when there is no competing reaction at the absorption site. Equations arederived which show that application of the Wagner-Nelson method to data which obey the two-compartment open model with first-order absorption allows accurate estimation of not only therate constant k, but also the parameters of the two-compartment open model, namely k~2, k21 ,and ket. In the example given, this new method was more accurate than the classical "feathering"or "back-projection" method. The appropriate criterion for "collapsing" the two- to the one-compartment open model is given. In cases where the one-compartment open model applies, andabsorption is first order but abruptly ceases after some time, it is shown that k a may be accuratelyestimated by application of the Guggenheim method to the Ar/V values calculated for the absorptionphase.
KEY WORDS: Wagner-Nelson method; absorption rate constant; one-compartment openmodel; Loo-Riegelman method; two-compartment open model; competing reactions atabsorption site.INTRODUCTIONThe method of Wagner and Nelson (1,2) as originally published,appeared to provide (a) plots of amount of drug absorbed per unit volumeof distribution vs. time and (b) plots of percent of drug absorbed vs. time.The method was not designed or claimed to be a method to determine an"absorption rate constant." Wagner and Nelson (1) stated: "When thecumulative percentages absorbed are plotted against time, the resultingplots may contain linear segments ; the slope of such a linear segment is theabsorption rate in percent/hour. If the plot is curved, or contains curved orSupported in part by Public Health Service Grant 5-P11-GM1555%1College of Pharmacy and Upjohn Center for Clinical Pharmacology, The University ofMichigan, Ann Arbor, Michigan 48104.2Address reprint requests to Dr. John G. Wagner, Upjohn Center for Clinical Pharmacology,The University of Michigan, Ann Arbor, Michigan 48104.469
9 1974 Plenum Publishing Corporation, 227 West 17th Street, New York, N.Y. t001 I. No part of this publicationmay be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical,photocopying, microfilming, recording, or otherwise, without written permission of the publisher.
linear segments, it may often be resolved to yield the components of therate
d %At~dr."
et al.
(3), Perrier and Gibaldi (4), and Leeson andWeintraub (5) have discussed problems that arise in estimating "absorptionrate constants" when the drug is absorbed and also simultaneously lost toan extravascular compartment via either a parallel first-order or a zero-orderprocess. Loo and Riegelman (6) applied the Wagner-Nelson method (1)to data which obviously obeyed the two-compartment open model withboth first-order and zero-order input to the central compartment and stated :"It appears that both the bi-exponential and the occasional appearance ofmaxima are artifacts of the numerical method."The method of Loo and Riegelman (6) requires that the drug be adminis-tered intravenously before plasma concentration data obtained followingoral administration may be evaluated. The method of Wagner and Nelson(1) does not require such intravenous data. Since, intravenous data arefrequently not available, the use of the Wagner-Nelson method becomesattractive. It is shown that in the special case where data obey the two-compartment open model with first-order absorption (without a parallelcompeting reaction), application of the Wagner-Nelson method allowsestimation of all the parameters of the two-compartment model.In resolving Wagner-Nelson "absorption" plots, the original numericalvalues obtained by the method should be utilized. The values should not beconverted to "percentage absorbed" values as originally published (1).This is important since if absorption abruptly ceases because of a "windoweffect" at the absorption site, the wrong asymptote would be used if theconversion to percentages were made.THEORETICAL
Relative Magnitude of Asymptotes by Wagner-Nelson (1) and Loo-RiegelmanMethods
If it is assumed that data obey the two-compartment open model, thenthe asymptote obtained by application of the Loo-Riegelman method (6) tothe oral data is given by equation 1 :
A+/V~ = ke, C~(t) dt
where Ao~ is the amount of drug absorbed to infinite time (which is equal to
where F is the fraction of the doses, D, which is absorbed), 1"1 is the volumeof the inner (central) compartment of the two-compartment model shown inScheme I below, kel is the elimination rate constant, and the integral is the
Application of the Wagner-Nelson Absorption Method
total area under the plasma concentration-time curve (taken as representa-tive of the area under the concentration-time curve of the central compart-ment).Under the same assumptions, the asymptote obtained by application ofthe Wagner-Nelson method (1) to the oral data is given by equation 2:
A~/Va .... = fl Cl(t) dt
(2)In equation 2, V~ ... and fl are given by equations 3 and 4, respectively:
Vd ... = (a/k21)V 1 = (kev/fl)V~
(3)fl = 89 +
k2~ + ka) -
[(k~2 +
k2~ + ko,) 2,- 4k21ka3 t/2}
(4)From equations 1, 2, and 3, one obtains the relationship given in equation 5 :Asymptote obtained by Loo-Riegelman method
= ~tk~ = koJ/~ (5)
Asymptote obtained by Wagner-Nelson methodEquation 5 will hold when there is no competing reaction at the absorptionsite, and for all cases of the two-compartment open model i.e., whenabsorption is nonuniform, or when absorption obeys uniform kinetics suchas first order.It follows that if one compares two oral treatments (e.g., two differenttablets or tablet vs. solution of the drug) and performs only the Wagner-Nelson method, then the ratio of the asymptotes obtained by means ofequation 2 is the ratio of the relative amounts of drug absorbed following thetwo treatments, provided that
remains constant for the subject.
The Two-CompartmentOpen Model with First-Order Absorption
If data obey this model (shown in Scheme I), then the "K" in the originalWagner-Nelson paper (1) becomes equivalent to "fl," as defined by equation4, since an estimate of "fl" is obtained from the terminal oral plasma con-centration data.The model is
C1Scheme I

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