Critical Analysis of “Flip-Flop” Phenomenon in Two‐Compartment Pharmacokinetic Model

Abstract

Computer simulations were used to examine the effect of first‐order absorption on the disposition of one‐ and two‐compartment model drugs. Two‐compartment systems that attain a clinically acceptable β‐phase after rapid intravenous injection were perturbed by introduction of drug via first‐order absorption. The validity of perceiving such a system as a potential “flip‐flop” model was tested by comparing the negative slopes of log‐linear plasma‐time profiles to known values for ka and β for various values of ka, k12, k21, and k21. Although most log‐linear plots showed excellent correlation coefficients (r2 > 0.996), their negative slopes (S) did not represent either k1 or β under various combinations. A similar consideration of the one‐compartment model enabled a comparison to be made between the two systems. Maximum negative errors were observed for both one‐ and two‐compartment drugs as ka → k2 or β, respectively. The value for S provided a good estimate of the absorption rate constant, ka, when k2 ≥ 2ka (one compartment) or β ≥ 2ka. The elimination rate constant (k2 or β) could be obtained from S for all one‐compartment and some two‐compartment drugs when the value of ka was approximately twice that of k2 or β. Large positive errors also were observed with certain two‐compartment drugs where the ratio of the four rate constants apparently linearized a nonlinear plasma profile. Conditions wherein S may be expected to approach β wherein S approaches ka are clearly defined.