Mária Ďurišová

Frequency response method in pharmacokinetics

The paper presents the demonstration of applicability of the frequency response method in a bioavailability study. The frequency response method, common in system engineering, is based on an approximation of the frequency response of a linear dynamic system, calculated from input-output measurements, by a frequency model of the system transfer function in the frequency domain. In general, the influence of the system structure on the form of the system frequency response is much more distinct than on the form of the system output. This is of great advantage in modeling the system frequency response instead of the system output, commonly used in pharmacokinetics. After a brief theoretical section, the method is demonstrated on the estimation of the rate and extent of gentamicin bioavailability after intratracheal administration to guinea pigs. The optimal frequency model of the system describing the gentamicin pathway into the systemic circulation and point estimates of its parameters were selected by the approximation of the system frequency response in the frequency domain, using a noniterative algorithm. Two similar estimates of the system weighting function were independently obtained: the weighting function of the selected frequency model and the weighting function estimated by the numerical deconvolution procedure. Neither of the estimates of the weighting function does decrease monotonously after the maximum of about 2.2–2.5 unit of dose·hr−1 recorded approximately 0.1 hr after drug administration. Both estimates show a marked additional peak approximately at 0.3 hr after administration and possible peaks in the further time period. We hypothesized that the loop found in the frequency response calculated and in the selected optimal frequency model, the high-order of this model, and several peaks identified in the estimates of the system weighting function indicated the complexity of the system and the presence of time delays. Three estimates of the extent of gentamicin intratracheal bioavailability obtained by the three different ways: directly from the calculated frequency response, calculated using the selected frequency model, and by the deconvolution method were 0.950, 0.934, and 0.907 respectively. Thus the conclusion can be made that gentamicin injected intratracheally to guinea pigs is almost completely available.

BUILDING A STRUCTURED MODEL OF A COMPLEX PHARMACOKINETIC SYSTEM WITH TIME DELAYS

This paper presents a description of the procedure for building a structured model of a complex pharmacokinetic system on using its transfer function. The example employed is that of the pharmacokinetic system based on gentamicin plasma concentrations after intravenous and intratracheal administration to guinea pigs, describing the pathway of the drug into the systemic circulation after the extravascular injection mentioned. The structured model selected consisted of a submodel of a proportional linear subsystem, two submodels of simple linear dynamic subsystems with time constants of 0.135±0.065 hr (95% I.C.) and 0.052±0.288 hr, submodels of parallel subsystems with time delays of 0.254±0.046 hr and 1.135±0.288 hr, connected in serial. Two estimates of the mean residence time of the total amount of gentamicin in the system, i.e. 0.347 and 0.335 hr, were obtained, based on the system frequency and structured model, respectively. From the methodological point of view, our paper demonstrates the efficiency of combination of modelling in the frequency and in the time domain, designed to facilitate studies of pharmacokinetic systems.

Modeling in Frequency Domain Used for Assessment of In Vivo Dissolution Profile

AbstractPurpose. To present a model-dependent approach for the assessment of the in vivo drug dissolution profile based on in vitrodata for the multiple unit dosage form, as an alternative to the numerical method proposed in the study by Hayashi et al, Pharm. Res. 12:1333−1337 (1995). Methods. The data for aspirin granules administered to healthy subjects obtained in the above mentioned study were re-evaluated. The subject dissolution system was considered to consist of two subsystems connected in series, i.e. the subsystem describing the gastric-emptying process and the subsystem describing the intestinal dissolution process. The frequency response method was used to model the subject dissolution system. Results. The model in vivodissolution profile of aspirin, assessed as the integral of the model weighting function of the subject dissolution system, was in agreement with the in vivo cumulative absorption profile calculated by the Wagner-Nelson method. Conclusions. Comparison of dynamic properties of the subject dissolution system with the subsystem describing the gastric-emptying process yielded quantitative confirmation of the decisive role of the gastric-emptying process in the in vivodrug dissolution after administration in the multi unit dosage form.

CXT-MAIN: a software package for determination of the analytical form of the pharmacokinetic system weighting function

A new procedure specific for the determination of the analytical form of the model weighting function of a complex multicomponent pharmacokinetic system with or without a shunt and time delays is described. The procedure is based on the theory of linear dynamic systems and on a circulatory pharmacokinetic model of the living body. The model transfer function of the system under study was obtained by the frequency response method in the form of the ratio of two frequency dependent polynomials. Subsequently, the technique of the partial fraction inversion was employed to determine the analytical form of the model weighting function. Two examples from bioavailability studies in pharmacokinetics are given. The first example presents two estimates of the model weighting function of a pharmacokinetic system obtained by the new procedure and by a polyexponential deconvolution method. To compare these results, two models of the measured system output were determined using the two estimates of the model weighting function, the actual system input and a convolution method. The model weighting function obtained by the new procedure yielded a better model approximation of the output data than that obtained by the polyexponential deconvolution method. The second example, using the new procedure, presents the determination of the model weighting function of such a system that the deconvolution methods, commonly used in pharmacokinetics, cannot be applied to.

CXT: a programme for analysis of linear dynamic systems in the frequency domain

In this paper, the computer programme CXT (CompleX Tools for Linear Dynamic System Analysis), using the frequency response method, is described and exemplified. The method is based on the approximation of the frequency response of the linear or linearised dynamic system, measured or calculated from input-output measurements, by the frequency model of the system transfer function in the form of the ratio of two frequency-dependent polynomials. The form of the programme is sufficiently general to permit application in many areas, e.g., in modelling linear or linearised dynamic biological systems consisting of several subsystems arranged in serial and/or parallel fashion, with or without time delays. The programme is a menu-driven software taking data from a keyboard or disk file to produce outputs on a screen, printer, or disk file in tables and plots. The programme can run interactively or in an automatic tutorial mode, under DOS and/or WINDOWS. Numerical examples are taken from pharmacokinetics and indocyanine green liver function tests.

Irradiation of the head by 60Co opens the blood-brain barrier for drugs in rats.

The passage of 6 model drugs; acetylsalicylic acid, chloramphenicol, ethimizol, carbisocaine, heptacaine, and diazepam, through the blood-brain barrier, was determined in unirradiated control rats and in animals 1, 3, and 7 days after irradiation of the head only with a dose of 25 Gy from a60Co source. The brain uptake index (BUI), which compares the uptake of the test substance with that of3H2O 5 s after their injection into the common carotid artery, was significantly increased in comparison with unirradiated controls 7 days after irradiation, for all substances tested except for ethimizol. For acetylsalicylic acid and chloramphenicol it was also significantly increased in the other time intervals. The less lipophilic substances showed a greater relative increase of BUI than the more lipophilic ones.

System-approach methods for modeling and testing similarity of in vitro dissolutions of drug dosage formulations

System-approach based modeling methods are used to model dynamic systems describing in vitro dissolutions of drug dosage formulations. Employing the models of these systems, model-dependent criteria are proposed for testing similarity between in vitro dissolutions of different drug dosage formulations. The criteria proposed are exemplified and compared with the criterion called the similarity factor f(2), commonly used in the field of biomedicine. Advantages of the criteria proposed over this factor are presented.

Pharmacokinetics of carbisocaine in rats and mice

Summary[14C]carbisocaine, N-(2-(2-[1-14C]-heptyloxyphenylcarbamoyloxy)-propyl)-diethylammonium chloride was administered to male Wistar rats, weighing 180–210 g IV in doses of 0.425, 1.425, 2.425 or 4.425 mg/kg or orally in a dose of 2.425 mg/kg. Extraction of carbisocaine from alkaline media into n-heptane was used for assessment of the unchanged drug in plasma, organs and excreta in predetermined time intervals. The two-way analysis of variance confirmed the insignificant effect of subject variability of experimental animals (p > 0.05) on plasma data after IV administration. Plasma data following the IV administration were approximated by a linear open two-compartment model with elimination from the central compartment. Regression analysis indicated linearity between carbisocaine plasma AUC and the IV administered dose within the range tested. The following model parameters were obtained: elimination half-life 161.2±37.5 min, total body clearance 59.5 ml/min/kg, distribution volume in steady state 5616.2 ml/kg and mean residence time 96.7 min. The systemic availability of the orally given carbisocaine was 45.2%, assessed by AUCpo/AUCiv (0–360 min). The brain uptake index of carbisocaine in relation to3H2O was 57.7±3.9%. Whole body autoradiographs of mice injected with [14C] carbisocaine documented accumulation of14C in gall and urinary bladder and in the gut contents and the effective placental barrier against carbisocaine and its metabolites.

Pharmacokinetic study of stobadine.

The aim of this paper is to provide a brief overview of most important results of stobadine kinetic studies in rats, dogs, and human volunteers. In these studies, stobadine dihydrochloride and stobadine dipalmitate was used for intravenous and oral administration, respectively. To evaluate kinetic properties of stobadine and its metabolites, TLC, HPLC, GLC, GC-MS, radiometric, and fluorometric methods were developed and used.

CXT-COMPLEX TOOLS FOR FREQUENCY DOMAIN ANALYSIS OF DYNAMIC SYSTEMS

The frequency response method, based on the approximation of the frequency response of the linear dynamic system by the model of its transfer function in the form of the polynomial ratio, is implemented in our software CXT-(CompleX Tools for Linear Dynamic System Analysis). After a very brief theoretical section, the CXT program is demonstrated on the estimation