Oral and IV dosing: a method to determine the compartment of drug elimination for two-compartment models.

It has been shown previously that it is impossible to measure the volume of distribution at steady state conclusively for a multicompartment system from an iv bolus dose only. The problem lies in deciding from which compartment elimination of the drug occurs in the compartmental model. In this paper a new modelling strategy is examined whereby the compartment of elimination may be identified uniquely for the case of two-compartment models. The two models examined predict different profiles in the absorption phase of an oral profile. An in vivo data set is provided that favours a peripheral elimination explanation of its observed pharmacokinetics, based on the 'goodness of fit'.

Lumping of whole-body physiologically based pharmacokinetic models.

Lumping is a common pragmatic approach aimed at the reduction of whole-body physiologically based pharmacokinetic (PBPK) model dimensionality and complexity. Incorrect lumping is equivalent to model misspecification with all the negative consequences to the subsequent model implementation. Proper lumping should guarantee that no useful information about the kinetics of the underlying processes is lost. To enforce this guarantee, formal standard lumping procedures and techniques need to be defined and implemented. This study examines the lumping process from a system theory point of view, which provides a formal basis for the derivation of principles and standard procedures of lumping. The lumping principle in PBPK modeling is defined as follows: Only tissues with identical model specification, and occupying identical positions in the system structure should be lumped together at each lumping iteration. In order to lump together parallel tissues, they should have similar or close time constants. In order to lump together serial tissues, they should equilibrate very rapidly with one another. The lumping procedure should include the following stages: (i) tissue specification conversion (when tissues with different model specifications are to be lumped together); (ii) classification of the tissues into classes with significantly different kinetics, according to the basic principle of lumping above; (iii) calculation of the parameters of the lumped compartments; (iv) simulation of the lumped system; (v) lumping of the experimental data; and (vi) verification of the lumped model. The use of the lumping principles and procedures to be adopted is illustrated with an example of a commonly implemented whole-body physiologically based pharmacokinetic model structure to characterize the pharmacokinetics of a homologous series of barbiturates in the rat.

Quantitative structure-pharmacokinetics relationships: I. Development of a whole-body physiologically based model to characterize changes in pharmacokinetics across a homologous series of barbiturates in the rat.

As part of an overall program to develop a framework for evaluating the contribution of structural and physicochemical properties to pharmacokinetics, the distribution kinetics of nine 5-n-alkyl-5-ethyl barbituric acids in arterial blood and 14 tissues (lung, liver, kidney, stomach, pancreas, spleen, gut, muscle, adipose, skin, bone, heart, brain, testes) was examined after i.v. bolus administration in rats. The barbituric acids studied form a true homologous series; therefore any differences in pharmacokinetics, noted between congeners, can be directly linked to the increase in lipophilicity, resulting from the addition of a methylene group. A whole-body physiologically based pharmacokinetic model has been developed, assuming most of the tissues to be well-stirred compartments. Brain and testes, in which distribution for the lower homologues was permeability rate-limited, were represented by two compartments. For each homologue, the model parameters have been optimized, using the tissue concentration-time data. The initial distribution processes in the system were very rapid, making it quite stiff, and essentially over before the first samples were taken. A progressively increasing redistribution from lean tissues into adipose on ascending the homologous series was observed, characterized by a tendency for a progressive decrease in the magnitude of the concentration-time profiles for some of the lean and well-perfused tissues, an increase in the adipose concentration-time profile, and an increase in the time to reach the maximum adipose concentration. A shift from permeability rate limitation to perfusion rate limitation of the distribution processes for brain and testes, as well as an increase in the intrinsic hepatic clearance and decrease in the renal clearance with the increase of lipophilicity of the homologues, were quantified. An increase in the total unbound volume of distribution on ascending the homologous series was also observed. Muscle was found to be the major drug depot at steady state, accounting for approximately 50% of the total unbound volume of distribution, regardless of the lipophilicity of the homologue; the unbound volume of distribution of adipose increases more than 10-fold with the increase of lipophilicity.

Three-dimensional freehand ultrasound: image reconstruction and volume analysis.

A system is described that rapidly produces a regular 3-dimensional (3-D) data block suitable for processing by conventional image analysis and volume measurement software. The system uses electromagnetic spatial location of 2-dimensional (2-D) freehand-scanned ultrasound B-mode images, custom-built signal-conditioning hardware, UNIX-based computer processing and an efficient 3-D reconstruction algorithm. Utilisation of images from multiple angles of insonation, "compounding," reduces speckle contrast, improves structure coherence within the reconstructed grey-scale image and enhances the ability to detect structure boundaries and to segment and quantify features. Volume measurements using a series of water-filled latex and cylindrical foam rubber phantoms with volumes down to 0.7 mL show that a high degree of accuracy, precision and reproducibility can be obtained. Extension of the technique to handle in vivo data sets by allowing physiological criteria to be taken into account in selecting the images used for construction is also illustrated.

A low-cost modular oxygen-consumption device for small animals.

This paper describes a simple apparatus enabling the O2 consumption of small animals to be monitored. The system consists of a sensitive solid-state pressure transducer linked via a relay to a small peristaltic pump. While the animal breathes air in its closed chamber the CO2 expired is removed by an absorber; hence the pressure falls. The signal is sensed by the transducer triggering the pump to deliver a set volume of O2 to the chamber. The number of pump operations per unit time necessary to keep the system equilibrated is a measure of the O2 consumption rate. Each device is built as a module, up to four being mounted in one assembly controlled by a microcomputer. A balance control, priming switch, pump-volume setting, and electromagnetic counter are built into each front panel. Calibration is achieved be removing a known volume of air from the system with no animal present and counting the number of operations to return the chamber to equilibrium.

A simple force transducer flow meter system suitable for the Langendorff heart preparation.

This paper describes the construction of a simple flow meter for use in preparations such as the Langendorff heart. It enables perfusion of the test tissue to be performed at constant pressure, with the signal produced being immediately compatible with the Ormed range of recording equipment. It requires only simple electronics, without integrators or frequency counters, to produce an average flow rate value over 30-second intervals. Since it is positioned beneath the preparation, it is not susceptible to retrograde flow effects; it is also designed to produce no back pressure. Comparison is made between the device and several other commercially available products. Details are also given of a two-channel system, with minimal components, not requiring an amplifier section. The main aim with the device has been to keep the design simple but adequate.

Development of a twin-flap, porous ceramic mitral valve prosthesis.

The pressure drop in most existing cardiac valve prostheses is at least ten times greater than for healthy valves. Steady flow testing indicates that the causes are (i) poor orifice diameter/sewing ring diameter ratio; (ii) occluding mechanism causes obstruction in the region of highest blood velocity. A new mitral prosthesis was constructed to overcome these deficiencies. The significant features are (a) tubular construction to maximize flow area; (b) twin flaps with hinges well above the outlet to minimize obstruction; (c) divergent nozzle to aid pressure recovery. Prostheses were manufactured from porous alumina, promoting firmly anchored, thin tissue growth to reduce haemolysis and thromboembolism. Preliminary trials in mini-pigs show good valve function. The ceramic behaves especially well. Future models will use ceramic flaps to replace the delrin flaps used ast present, which encourage fibrin deposits.