PHYSICAL REVIEW E 66, 0219XX (2002) \e46 Fractal pharmacokinetics of the drug mibefradil in the liver J. Poite, R. Marsh, and J. Tuszytiski Department of Physies, University of Alberta, Edmonton AB, T6G 2J1, Canada (ceived 23 April 2002) ‘We explore the ramifications of the fractal geometry of the key organ for drug elimination, the iver. en [Pharmacokinetic data analysis. formalism is developed forthe use of combination of well sired Eveliécan and fractal compartments in the body. Perturbation analysis is carried out to obtain analytical solutions forthe rug concentration time evolution. These results are then fited to experimental data collected from ically instrumented dogs (se, A. Skerjanec eal, J. Pharm. Sei, 85, 189 (199S)] using the drug mibefradi The thus ‘obtained speciral fractal dimension has « range of values tha is consistent with the value found in indopen- dently performed ultrasound experiments on the liver, DOF: 10.1103/PhysRevE 66.0219 L INTRODUCTION Pharmacokinetics is concerned with the quantification of the fate of @ drug in the body [1]. It can reveal valuable information about the path of a drug, its volume of cistribu- tion, its metabolism, and eliminatioa [2]. Traditionally, pha rmavokinetic models involve compartmentalized systems, ‘where the invasion and elimination ofa drug from a partic lar compartment is modeled by a series of simple exponea- tials duc to the governing first-order chemical kinetics. ap- proach (3) The fundamental problem of pharmacokinetics is to math- matically describe the course of a drug through the body [4]. Conventionally, the spaces through which the drug trav- cls are divided into compartments, and the invasion and elimination of the drug ftom each compartment are ex- pressed in terms of the relevant kinatic rate constants. Any foreiun substance introduced into the body appears in the blood and then passes to other tissues or fuids by simple diffusion until itis metabolized andor eliminated. The ex- travaseulat compartments may include the gastrointestinal tract, the liver, urine, or sweat. Conventional phanmacokinet- ics treats the spaces through which a drug passes as indi vidual compartments connected in series or parallel. Each compartment is typically envisioned as @ homogencous en- tity that represents an average state [5] To understand the mechanics of a compartment model, we ‘may look atthe three-compartment example in Fig. 1, which depicts the movement ofa drug injected into muscult inter stitial tissue, From the muscle, the drug enters the blood and from there is reversibly transfered 10 the extravascular space. The kinetic coefficient ka represents elimination from the frst compartment, Ayp represents exeretion, and 435 and se; represent rates of transfer. The indices denote the direc- tion of transfer, $0 kp, indicates flow into the sesond come partment from the fist while ky indicates flow to compart- ‘ment three from compartment two, ete Pharmacological data generally consists of concentration versus time measurements for each compartment. Typical curves for pure absorption and pure elimination after a hotus dose Dy ate shown schematically in Fig. 2), Cathar wey sinuous mewn IRE eOaton, the combined concentration versus time curve takes the form 1063-651 /2002/66(29/0219XX(11}820.00 65 0219XX-1 PACS number(s): $2.39.-k, 05.45.Df, 61.43.Hly, 82.30.—b siven in Fig, 20. Initially, invasion is much larger than elimination, s0 the curve climbs steeply upward. Invasion then decreases while elimination increases until the two be- come equal, giving rise to the maximum compartment con- centration. After the peak value, both absorption and elimi= ration dectease and the curve slopes dowawards. In the Inajority of cases, the constant of absorption is much higher than the constant of elimination, and the absorption rate be comes negligible after the peck [6]. Such x eurve has been traditionally modeled by a sum of exponentials that works well for short to moderate times [6] One problem with the waditional models is that they rely fon the assumption of firsvorder kinetic processes, where each compartment is considered to be homogencous, of “vel steed." In other words, there i an intantanoous egui- librium reached after the appearance oF the drug in a com- partment, Numerous attempts to overcome this simplification have been made, including the development of parallel tube imoulels, dispersive models, the incorporation of physiologie cal attributes such s the perfusion of body tissues, and an ad hoc use of power functions of time [2,8]. Unfortmately, al these methods still have limitations [9], Recently, however, i has been proposed that fractal theory may be applied to phar- ‘macokineties [9]. Although fractal kinetics has been studied for some time and has been applied to the flow of blood in the body [10-12], it was not until 1996 thatthe techniques of fractal analysis were applied to pharmacokinetics [9,13]. Fo: example, MGheres [9] developed what he calls a hhomogeneous‘ieterogeneous distribution made! based on the fractal properties of blood flow: From a drug's site of administration, the blood isthe pre- dominant method of transport through the body to the dog's final destination, Conventionally, the blood is treated as a simple compartment, although the vascular system is highly com | y ir P i FIG. 1. Basic pharmacokinetic mode! fora drug ta i absorbed ‘nto muscle, distnbuted, and eventually eliminated by the blood, but reversibly transfered to the extravascular space ‘02002 The American Physical Society &J. FUITE, R. MARSH, AND J. TUSZYNSKI De @ tration, Concentration Time Thine FIG. 2. Typical pure elimination (2) and pure invasion (Il) curves. (b) Simultaneous invasion and elimination curve, ‘complex and consists of an estimated 96 000 kin of vessels (14), Recently, however, the fiactal nature of the vascular network has been described, providing a simple way to take the complex geometry of the vascular system into account U5]. Nurmerous studies have been done to apply fractals 10 general kinetic theory [16-19], but surprisingly litle work has been done on fractal pharmacokinetic theory (20,21), vir ‘wally none of it being quantitative. Consequently, the pur pose of this paper isto investigate the application of fractal theory to pharmacokinetics. In addition to providing an ex- periment for the treatment ofthe liver as a fractal object, we Aevelop here a practical kinetic description of the process of drug elimination from the bloodstream. To make the argu iment convincing we illustrate the model with an application toa particular dataset that was collected by Skerjanec et al {22} using the drug mibefradil on clinically instrumented dogs. ‘The objective of the first stidy performed by Skerjance etal. [22] was to assess the suitability of mibeffadil as a model for human pharmacokinetics. Mibeftadil isa calcium antagonist currently being developed to reduce ventricular fibrillation (23,24). Tam and co-workers foun tha, similar to drugs in humans, the kinetics of mibefradil ia dogs be- comes nonlinear with inereasing oral dose. Skerjanec etal [22] sited, however, that it was not possible to quantify the contribution of organs involved in presystemic metabolisin and their role in the nonlinear kinetic behavior of mibefiadil. To explore this nonlinearity further, Sketjanec et al [22] por formed a second, physiological study using four chronically instrumented female dogs ranging in weight from 19 to 24 kg, Three single oral doses of 1 3, and 6 mg/kg euch, a multiple oral dose treatment of 1.3 me/kg every 12 h for eight days, and a | mg/kg for 10 min intravenous dose into the cephalic vein were administered to each dog in random order, with a one-week break between treatments. Blood samples were drawn from catheters placed in the jugular vein, coronary artery, hepatic vein, and portal vein, providing a series of plasma concentration versus time profiles. The hypothesized path of mibefradil through the body of the dog is depicted in Fig. 3. Note that there is a feedback loop into the liver via the aorta The results of the study by Skerjanee et al. (22) showed that the liver isthe major site of drug elimination from the body. The conclusions of this study were that the nonlinear kinetics of mibetradil in dogs is mainly duc to dose and time-dependent reduction of hepatic clearance. AC present, the cause of this reduction is not known but several possic PHYSICAL REVIEW E 66, 0219Xx (2002) Brain ings eantid ety sey Intestines oral ver FIG. 3. Simplified diagram of the course of mibefinlthroush the boy bilities have been mentioned including nonlinear absorption andor elimination, and product inhibition that can lead to dose and time-dependent changes in elimination kineties, We believe that the fractal structure of the liver with the atten- dant kinetic properties of drug elimination may be respon- sible for some of the nonstandard behavier. TL FRACTAL STRUCTURE OF THE LIVER Jn an attempt to bring some aspects of physical analysis ro bear on the study of the pharmacokinetics of mibelradil, the physical structure of the live, the main site of the drug's metabolism [23,24] is selectively considered. It appears that in humans the liver isthe largest visceral orgen and it pos- sesses unustal microcirculatory pathways (25). tis supplied with blood by both the hepatic artery and the hepatic portal vein, thus being the fist structure to receive xenobiotically laden blood from the intestines [26] Elias [27] defines the liver asa continuous mess of paren chymmal cells tunneled by vessels through which venous blood flows on its way from the gut to the beast. The circu lation in the fiver can be divided into the mactocizeulatio, and the microcirculation. The former is comprised of the portal vein, hepatic artery, and hepatic veins, while the later consists of the portal vein, hepatic arterioles, and the siaus0- ids (25). The sinusoids are the specialized capillaries of the liver that form an uninterrupted three-dimensional network and are fully permeable to substances, This macrocirculation spans the axes of the liver while branching into successively smaller vessels. AC the anstom cal Jevel, there exist stall histological units, called lobules. rade up of an interlacing channel network of sinusoids sup- plied with blood and drug by the terminal ends ofthe portal venules and hepatic arterioles. Between the individual sinu- soids of the interior of lobule, one-ell-thick sheets of hepatocytes are interspersed [28,29]. Facing the blood spaces, the convoluted uptake surface of the hepatocytes ex- pds the blood-tissue interface by the presence of numerous 0219xX2> FRACTAL PHARMACOKINETICS OF THE DRUG ®) ® YF Fy yh Fol % aro y-aFo Conky aa FIG. 4. Asymmetric fractal branching model where fractions y and (I~ 7) of toal flow Fy are distibuted to daughter branches, shown for (2) ane bifurcation and (b) two bifurations ‘microvilli. Separating the hepatocytes andthe blood space, is 4 topologically complex endothelium lining that defines the ‘minute passages of the sinusoids. The fenestrae of the endo Frelium allow direct uecess of drug within the circulating plasma to the surface of the hepatocytes via the space of Disse. A very thin but functional and distinct extracellular space of the liver, comprising the space of Disse, exterior to the sinusoid, vee contains both collagen fibers and ground substance, zad wherein the microvilli of the hepatocytes ex- tend. Summarily stated, observations of the liver reveal an anatomically unique and complicated structure over a range of length scales designating the space where mibefradil me- tabotism takes place. Iti the special geometry ofthe microvascular system that first led researchers to postulate the fractal nature of regional flow networks. The vessels of one generation bifurcate to form vessels of the next generation in a continuous process towards smaller and smaller vessels. Furthermore, the geom- exry of the daughter branches is not random. Extensive te- search of the vessels feeding the kidney, lungs, and heart has shown that 2 scaling relation holds for branch length branch diameters, radius-to-length ratios and intra-arterial pressures [12]. Consequently, the low into tissues isnot ran- domly distributed among the regional vessels. A distinguish- ing characteristic of vascular bifurcation is that the (wo daughters of any generation are asymmetric, with one reesiv- ing a fraction y of the flow and the other a fraction (1 — 7) Figure 4 shows the results for one and two bifurcations. This way, the fraction of flow in a given branch can be caleulated as a fraction of initial low Fp, generation number ‘mand flow parameter . Here, & takes integer values from 0 to n [28] such that YF y aw The frequency of each value is An &)! ® and the mean flow aftern generations is Fo - o Simulations carried out with the use of m equal to 15 (whieh corresponds to 32 768 terminal branches) resulted in distributions that were slightly skewed to the right, which is consistent with experimental data [12], The discovery and ‘quantification of the fractal nature of regional blood flow has PHYSICAL REVIEW E 66, 0219XX (2002) led to new investigations and theories in many areas of anatomy, physiology, and body mechanics. For example, the spatial heterogeneity that exists within isogravtational planes has traditionally been atibuted to randomness. The discovery ofthe fractal nature ofthe blood vessels, however, indicated that the distibution of flow within an oman may be fractal as well. In fact, this phenomenon has been observed in vessels supplying the lungs, heart, and liver 1228.29} By the observations that the liver basa hierarchical stuce ture with complications at many length seals fiom the order of its macroscopic diameter to the oder ofthe macromolect Jac makeup of the matrix within the space of Disse, itis hypothesized that the liver is u fractal-ike object. That the structure of, and blood flow heterogeneity in, the liver and other visceral organs is fractal, hes been suggested and at times experimentally tested before, especially in flelds out side of pharmacology and pharmacokinetics [1012.30.31 For example, by means of analysis of ultrasonic wave see tering from calf liver tissue, Javanaud [32] measured the ffactal dimension of the liver as approximately d=2 over a wavelength domain of 0.15-1.5 mm. Correspondingly, the liver, a experienced by the drug mibetrail, will be assumed haere as being well approximated by a fractal between experi- mentally relevant length scales [20]. IIL IMPLICATIONS OF ORGAN FRACTALITY ON PHARMACOKINETICS A deeper analysis of the metabolism of mibefradi in the liver requtes a description of transport phenomend ‘with chemical reaction in comprex meio, This cas be performed ty means of fatal geomety using two basic exponents the facta and sidithnemors Tennst be sitessed, however, that a proper levél of approximation for reation-dTusion phevomens in complex frictal mosia is stil an open ce The application of regional blood flow heterogeneity to pharmacokinetics has resulted "in the homogeneous Feterogeneous distribution model developed by Miers: [9], who divided the distribution of drugs in the body into two eategories First, hat which oecurs under homogencoix (Cll sted) sonditions, and second, thot wich curs under heterogeneous ("ander stied") conditions. The Hist type of distribution takes place in the upper half of Fig. 5. where the rte of flow is simpy Fy-The second ype of {Exirbuson takes place inthe lower hall of the das, in the dcp tissues, where the vascular bnchng is profse, ‘Dastiption of distbution under homoyencous cemdtons can be done using clasia! knee, while focal kinetin Should be applied to distrbutio under heterogeneous con tions. Thus the combined, comprehensive model for the tribution of a drug would involve both types of kinetin Before examining the form ofthis mode, we need (inves: tigate the nature of focal Kneis Classi transport theories and the resuling mas-acton ines aplcable to Euclidean souctres not apply (0 transport phenomena in complex and disordered media, The fsometicalcogsttinis imposed by. the. heterogencots Fractals srctre of the iver strongly modiy clusion O219KX-3