A computer program for calculating distribution parameters for drugs behaving nonlinearly that is based on disposition decomposition analysis.

Evaluation of drug distribution into peripheral tissues is of considerable importance in pharmacokinetic analysis, especially for drugs whose sites of action are in the tissue pool. The tendency of drugs to distribute in peripheral tissues has been described in terms of volumes of distribution (Vd),' distribution or intercompartmental clearance (cLd),2*3 and mean residence (MRT,) and mean transit (MTTT) times in the peripheral tissues.4-6 Among these parameters, the steady-state Vd (Vd,,), CLd, and MTTT are dose independent in pharmacokinetic systems with linear tissue distribution and nonlinear central elimination.' When it is desirable to estimate Vd, for drugs behaving linearly, approaches proposed by Riegelman et al. (two-compartment model)? by Wagner (polyexponential equations)? by Benet and Galeazzi (areajmoment analysis),'O by Kowarski and Kowarski (infusion to steady-state),ll and curve-fitting procedures such as nonlinear regression analysis using NONLIN are feasible.12 For drugs behaving nonlinearly, simultaneous curve fitting may be the only technique available for calculating Vd,. This technique, however, is model dependent (i.e., a specific number of peripheral compartments must be ascertained for the drug). Recently, based on disposition decomposition analysis (DDA),13 a method (DDA method) was proposed for calculating Vd,, CLd, and MTTT of drugs that undergo linear tissue distribution and are eliminated nonlinearly from the central compartment.3.7 In contrast to the curve-fitting procedures, this method is a "noncompartmental" approach. (3) In eqs 1-3, V, is the central volume of distribution and h(t) is the distribution function for drug return to plasma from all peripheral sites.l3 Thus, to estimate these three dose-independent parameters, the DDA method requires determination of V, and h(t) from intravenous (iv) data. An algorithm has previously been proposed to calculate h(t).13 However, no computer program is available in the literature. The purpose of this paper is to describe a personal computer-based pharmacokinetic program (DDAO) for calculating h(t), Vd,, CLd, and MTTT for drugs behaving nonlinearly and to illustrate its use. Hardware-Program DDAO was written in FORTRAN and developed for use on IBM Personal Computers or compatibles with at least 640 K of memory and one floppy fisk drive. The program can be readily translated to the BASIC or C language. Mathematical and Computational Methods-A numeric approach for estimating the distribution function, h(t), has been suggested previously by Veng-Pedersen13 and is briefly summarized below for the convenience of the readers. If Cl(t) and CZ(t) represent plasma concentrations at time t, after two different iv bolus doses (DI and D2, and D1 …