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PubMed1995

Determination of multiply labeled serine and glycine isotopomers in human plasma by isotope dilution negative-ion chemical ionization mass spectrometry.

A gas chromatography/negative-ion chemical ionization mass spectrometry method is presented to measure the isotopic enrichment of multiple serine and glycine isotopomers. The amino acid N-heptafluorobutyryl n-propyl ester derivatives were used. The method had good analytical linearity between 10 and 800 microg mL-1 and both precision and accuracy were 5% for plasma amino acids. Sensitivity permitted analysis of 100 pg amino acid on column. The method was applied to metabolic studies of the serine to glycine interconversion in humans. (alpha-15N)serine and (1,2-13C2)glycine were given as a single intravenous bolus to six healthy male subjects. Plasma concentration of glycine and serine were determined after addition of (alpha-15N,1,2,3-13C3) serine and (alpha-15N,1,2-13C2)glycine as internal standards to 500 microL of plasma. Since glycine and serine are rapidly interconverted by hepatic serine hydroxymethyl transferase, the resultant tracer spectrum requires deconvolution of the enrichment of four isotopomers of each amino acid. Deconvolution of the ion abundance ratios to yield tracer-to-tracee ratios for each isotopomer was done using Brauman's least squares approach.

Gas Chromatography-Mass Spectrometry↗
PubMed2005

Characterization of cysteinylation of pharmaceutical-grade human serum albumin by electrospray ionization mass spectrometry and low-energy collision-induced dissociation tandem mass spectrometry.

Three samples of albumin derived from human plasma (pharmaceutical grade, HSA) obtained from different commercial sources were investigated for their micro-heterogeneities by means of electrospray ionization (ESI) ion trap mass spectrometry (ITMS). The study covered MS analyses of the intact proteins as well as on the tryptic peptide level. The intact protein samples were analyzed without any separation step except for simple desalting. With these samples we observed in the positive ion ESI mass spectra that the multiply charged ion signals of HSA consisted of a number of fully or partly resolved peaks with relative intensities depending on the analyzed sample. The non-modified form of HSA was detected in the three HSA preparations at m/z values of 66448 +/- 3.6, 66450 +/- 0.6 and 66451 +/- 3.2 ([MH]+), respectively. The value calculated from the amino acid sequence was 66439. The second compound present with high intensity (in two cases the base peak in the deconvoluted mass spectrum) is interpreted as a modified HSA, and the molecular mass increase in relation to the unmodified HAS was between 116 and 118 Da (m/z of 66 564, 66 567 and 66 569), suggesting the presence of a covalently bound cysteine residue. A further peak in the deconvoluted ESI spectra was found in all three samples with rather low signal/noise ratio at m/z 66 619, 66 621 and 66 613, respectively, which may correspond to a non-enzymatic glycation described in the literature. The verification of the proposed covalent HSA modifications was subsequently done on the peptide level using high-performance liquid chromatography (HPLC)/ESI-MS and HPLC/ESI-MS/MS including low-energy collision-induced dissociation (CID). Prior to the tryptic digestion, the HSA samples were alkylated without a prior reduction step. Following this procedure we detected peptides of the sequence T21-41 that included the Cys-34 residue in both forms: cysteinylated (m/z 639.15 [M+4H]4+) as well as vinylpyridine-alkylated (m/z 635.69 [M+4H]4+, which means in its previously native free SH form). In the next step on-line LC/ESI low-energy CID MS/MS experiments were performed to verify these two proposed structures. By means of MS/MS analysis of the mentioned ions the described modification (cysteinylation) at the Cys-34 residue could be proven. This abundant modification of HSA in pharmaceutical-grade preparations could be unambiguously identified as cysteinylation at the Cys-34 residue. On the other hand, the proposed non-enzymatic glycation was not detectable on the peptide level in the on-line HPLC/ESI-MS mode, maybe due to the low concentration in the three samples under investigation.

Amino Acid Sequence↗
PubMed2006

Direct infusion electrospray ionization mass spectra of crude cell extracts for microbial characterizations: influence of solvent conditions on the detection of proteins.

Direct infusion electrospray ionization mass spectrometry (DIES-MS) of crude bacterial extracts is a rapid method that can be used to characterize microbial cells. Phospholipids, metabolites, and proteins can be detected rapidly with minimal sample preparation. However, several factors influence the detection of signals in such high-throughput analyses. We studied the influence of solvent conditions, including the organic content and pH of the solvent, on the extraction and subsequent detection of signals in DIES-MS, with a view to improving the detection of protein signals. Unfractionated cell extracts from three strains of the Gram-negative Escherichia coli (including one encoding a recombinant green fluorescence protein), and the Gram-positive Bacillus sphaericus and B. subtilis were investigated. Both pH and the organic content of the solvent were found to influence the spectral information as observed from principal component analysis of the spectral data. A polar solvent with higher organic content resulted in the extraction of phospholipids that overtly dominate the spectral information. Decreasing the organic content of the extraction solvent resulted in the improved detection of protein peaks. Altering the pH of the extraction solvent resulted in different protein profiles from the same bacterium, as observed after spectral deconvolution. In addition, the protein profiles were also different when using different organic solvents. Spectral deconvolution showed several protein peaks that had mass-based homology with those in protein databases for the (sequenced) organisms studied. These results suggest that a combination of solvent conditions can be used to generate protein profiles rapidly that when combined can provide additional valuable proteomic information.

Bacillus↗
PubMed2006

Strategies to avoid false negative findings in residue analysis using liquid chromatography coupled to time-of-flight mass spectrometry.

Liquid chromatography coupled to orthogonal acceleration time-of-flight mass spectrometry (LC/TOF) provides an attractive alternative to liquid chromatography coupled to triple quadrupole mass spectrometry (LC/MS/MS) in the field of multiresidue analysis. The sensitivity and selectivity of LC/TOF approach those of LC/MS/MS. TOF provides accurate mass information and a significantly higher mass resolution than quadrupole analyzers. The available mass resolution of commercial TOF instruments ranging from 10 000 to 18 000 full width at half maximum (FWHM) is not, however, sufficient to completely exclude the problem of isobaric interferences (co-elution of analyte ions with matrix compounds of very similar mass). Due to the required data storage capacity, TOF raw data is commonly centroided before being electronically stored. However, centroiding can lead to a loss of data quality. The co-elution of a low intensity analyte peak with an isobaric, high intensity matrix compound can cause problems. Some centroiding algorithms might not be capable of deconvoluting such partially merged signals, leading to incorrect centroids.Co-elution of isobaric compounds has been deliberately simulated by injecting diluted binary mixtures of isobaric model substances at various relative intensities. Depending on the mass differences between the two isobaric compounds and the resolution provided by the TOF instrument, significant deviations in exact mass measurements and signal intensities were observed. The extraction of a reconstructed ion chromatogram based on very narrow mass windows can even result in the complete loss of the analyte signal. Guidelines have been proposed to avoid such problems. The use of sub-2 microm HPLC packing materials is recommended to improve chromatographic resolution and to reduce the risk of co-elution. The width of the extraction mass windows for reconstructed ion chromatograms should be defined according to the resolution of the TOF instrument. Alternative approaches include the spiking of the sample with appropriate analyte concentrations. Furthermore, enhanced software, capable of deconvoluting partially merged mass peaks, may become available.

Algorithms↗
PubMed1993

Noncompartmental and compartmental modeling of the kinetics of carbon-11 labeled pyrilamine in the human brain.

The kinetic pattern of a 11C-labeled histamine H1 receptor antagonist, [11C]pyrilamine, was investigated in the human brain by factor analysis of dynamic PET studies. Tissue time activity curves were also processed by compartment model curve fitting preceded by deconvolution analysis. Factor analysis revealed two statistically significant and physiologically meaningful kinetic patterns: one for specific and another for nonspecific binding of the radioligand. From these two factors a compartment model containing two tissue compartments (one for specific binding and another for nonspecific binding and free ligand) was constructed. The two-compartment model was also supported by the impulse response function, which was obtained by deconvolution and showed two components. The factor image constructed from factor two demonstrated a distribution pattern characteristic for brain regions rich (frontal, parietal, and temporal lobes) or poor (occipital lobe and cerebellum) in H1 receptors. Blockade of H1 receptors with unlabeled pyrilamine, diphenhydramine, or hydroxyzine caused a significant reduction of this factor. Blockade produced no significant changes in factor one representing nonspecific binding. We conclude that the kinetics of [11C]pyrilamine in the brain can be described by two tissue compartments, one related to the distribution of the H1 receptors. Factor analysis of dynamic studies can be used to locally separate these two compartments, for identification of regions rich and poor in H1 receptors and for noninvasive quantitative investigation of the effects of H1 receptor blockers such as pyrilamine, diphenhydramine, or hydroxyzine.

Adult↗
PubMed2000

Pulsed Electric Linear Dichroism of Triphenylmethane Dyes Adsorbed on Montmorillonite K10 in Aqueous Media.

Electric linear dichroism (ELD) spectra of two cationic triphenylmethane dyes, crystal violet (CV) and malachite green (MG), bound to sodium montmorillonite K10 (MK-10) were studied at 20 degrees C in aqueous media at two mixing ratios, D/S, of 0.10 and 0.24 in the 700- to 400-nm wavelength region and in the applied electric field strength range between 0 and 3 kV/cm. The specific parallel and perpendicular dichroism (Delta A( ||)/A and Delta A( perpendicular)/A) spectra of dye-adsorbed MK-10 suspension were measured at a fixed field strength with an apparatus equipped with a 512-channel photodiode array detector. By changing the field strength over a wide range, a series of the reduced dichroism values of the bound dyes were measured at a fixed wavelength. By fitting these dichroism values to theoretical orientation functions, the intrinsic reduced dichroism (Delta A/A)(int) spectra at the limiting high fields (ELD spectrum) were determined for CV and MG bound to MK-10. No appreciable difference was observed at the two D/S values. The ELD spectra of these bound dyes are undulatory but never constant, throughout their absorption region; thus, the dye plane does not lie flatly either on the surface or between layers of MK-10 particle. The isotropic absorption spectra, A, of bound CV and MG were each deconvoluted to eight partial absorption bands, which were grouped into three differently polarized transitions, i.e., one out-of-plane and two mutually perpendicular in-plane. The optical transition dipole moment direction of each group was found to make a considerable angle with respect to the symmetry axis of the disklike MK-10 particle, whose plane (or surface) tends to orient toward the applied electric field at the limiting high fields. By simulating the observed ELD spectra of bound CV and MG with those deconvoluted bands, the roll, tilt, and inclination angles of both dyes were evaluated quantitatively with a new analytical method. The average angles (+/-θ(R), +/- θ(T), |θ(N)|) are -(34-47) degrees, 34 degrees, and 51 degrees for bound CV and -44 degrees, 32 degrees, and 53 degrees for bound MG at two D/S values; thus, the triangular plane of each dye is rolled as well as tilted with a large inclination angle. Copyright 2000 Academic Press.

Journal Article↗
PubMed2000

X-Ray Photoelectron Spectroscopy Analysis of Di-(2-ethylhexyl) Phosphoric Acid Activated Membranes.

Surface chemical characterization of activated composite membranes, which consist of a polyamide/polysulfone support containing different amounts of di-(2-ethylhexyl) phosphoric acid as carrier, was performed by X-ray photoelectron spectroscopy (XPS) in order to obtain information about the nature of the chemical bonding between the carrier and the membrane top layer. XPS spectra of the top layer of the polymeric support (polyamide) show bands in the C 1s, N 1s, O 1s, and P 2p regions. The N 1s and O 1s signals of the polyamide layer were asymmetric and could be deconvoluted in two peaks that correspond to the coexistence of free and hydrogen bonded polyamide. To support this assignment, primary amides such as benzamide and n-butyramide, which can associate themselves forming hydrogen bonding, and a tertiary amide, N-benzoyl morpholine, unable to form hydrogen bonding, were also studied by XPS. The N 1s asymmetric signals of benzamide and n-butyramide were deconvoluted in two peaks due to the coexistence of free and hydrogen bonded species, while the N 1s signal of N-benzoyl morpholine is symmetric and corresponds to the existence of free amide alone. As a result of the addition of di-(2-ethylhexyl) phosphoric acid to the polymeric matrix, the N 1s signal intensities decrease, while the P 2p signal intensities increase with carrier concentration to a maximum corresponding to surface site saturation. Upon acid addition, the polyamide was protonated and an expected chemical shift of the N 1s signal to higher binding energies was observed due to the increase of the positive charge of the nitrogen atom. This type of chemical interaction allows to fix the carrier in the membrane without its complete immobilization. On the other hand, the surface concentration of N and P, determined by XPS, indicates that a concentration of 400 mM of the carrier in the casting solution is sufficient to saturate the surface of the membrane. Copyright 2000 Academic Press.

Journal Article↗
PubMed2002

Separation of intra- and extramyocellular lipid signals in proton MR spectra by determination of their magnetic field distribution.

In skeletal musculature intramyocellular (IMCL) and extramyocellular lipids (EMCL) are stored in compartments of different geometry and experience different magnetic field strengths due to geometrical susceptibility effects. The effect is strong enough to---at least partly---separate IMCL and EMCL contributions in (1)H MR spectroscopy, despite IMCL and EMCL consisting of the same substances. The assessment of intramyocellular lipid stores in skeletal musculature by (1)H MR spectroscopy plays an important role for studying physiological and pathological aspects of lipid metabolism. Therefore, a method using mathematical tools of Fourier analysis is developed to obtain the magnetic field distribution (MFD) from the measured spectra by deconvolution. A reference lipid spectrum is required which was recorded in tibial yellow bone marrow. It is shown that the separation of IMCL contributions can be performed more precisely---compared to other methods---based on the MFD. Examples of deconvolution in model systems elucidate the principle. Applications of the proposed approach on in vivo examinations in m. soleus and m. tibialis anterior are presented. Fitting the IMCL part of the MFD by a Gaussian lineshape with a linewidth kept fixed with respect to the linewidth of creatine and with the assumption of a smooth but not necessarily symmetrical shape for the EMCL part, the only free fit parameter, the amplitude of the IMCL part, is definite and subtraction leads to the EMCL part in the MFD. This procedure is especially justified for the soleus muscle showing a severely asymmetrical distribution which might lead to a marked overestimation of IMCL using common line fitting procedures.

Extracellular Space↗
PubMed2003

Phenomenological definition of response times with application to metabolic reactions.

The metabolic response time, i.e. the delay the system introduces in the response to an input flux, is considered. A novel phenomenological definition is presented, which is valid for any kind of behavior, including transitory or permanent oscillatory responses. In order to calculate the response time of single-input systems, output fluxes have to be deconvoluted with the input flux. The bases for this are established. The resulting function (unit impulse response in time-invariant linear systems) is transformed by subtracting its final state, taking the absolute value and normalizing by the resulting area, so that a norm can be applied that weights the response at every time. This response time can also be interpreted as an average. It coincides with the transition (characteristic) time of an output flux, provided that the input is performed instantaneously (step function). A strictly non-negative response function is needed for the response time to be interpreted as a mass balance. A simple example is used to study the deviation otherwise. The method is advantageous in that it provides clues on the phenomenological behavior of biochemical systems. For example, deconvolution reveals the intrinsic oscillation-generating mechanism of an allosteric enzyme, which becomes hidden when the input flux increases in a slow way. This is illustrated by means of a model.

Animals↗
PubMed1994

Glucose diffusion coefficients determined from concentration profiles in EMT6 tumor spheroids incubated in radioactively labeled L-glucose.

A method for performing and evaluating autoradiography of diffusible 14C labeled substances in multicellular tumor spheroids is presented that allows one to obtain a diffusion coefficient of the substance investigated from each individual spheroid. Application of the method with 14C labeled L-glucose resulted in a glucose diffusion coefficient of 5 x 10(-6) cm2/s. It also revealed problems of the method at very short incubation times of about 10 s or less. These problems are most likely caused by the large penetration depth of beta particles irradiated by 14C labels (as compared to 3H labels) which tends to transform steep 14C concentration gradients into much more shallow optical density gradients during exposure. This transformation can be corrected for by deconvolution of the recorded optical density distributions. Basic data and mathematical tools necessary for the process of deconvolution are presently being developed. It is planned to use this method for determining diffusion coefficients of other substances of interest. One such group of substances are the metabolic waste products, most importantly lactate. Another group consists of larger molecules, e.g. peptides and comprises the various growth factors important in tumor biology. Since for members of this latter group little is known about their velocity of penetration into tissue, model calculations may be applied to predict a range of incubation times suitable for determining diffusion coefficients. Moreover, the algorithms for data analysis will have to be modified to allow for receptor binding of the substance under study.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Deconvolving out indicator smearing in the right ventricle facilitates left-to-right shunt quantitation.

A simple algorithm is developed to enhance the resolution of components of multimodal pulmonary radiohistograms. Based on the assessed right ventricular ejection fraction (RVEF), it deconvolves out the effect of indicator smearing in the right ventricle on the heart rate samples of the pulmonary radiohistogram, ck. The output is the ideal curve, c'k = ck/RVEF--(1-RVEF).ck-1/RVEF, that would be obtained if RVEF equalled unity. Since the formula is not a recursive one, it does not suffer from error propagation pertinent to numerical deconvolution. Once RVEF is known, implementation of the algorithm is simple. If RVEF is not known accurately it may be replaced with its upper estimate, RVEFup > RVEF, yielding a partial deconvolution of the curve. When applied to studies of patients with left-to-right shunt the method improves the accuracy and lessens the interobserver variation of the Maltz-Treves method.

Adult↗
PubMed1987

Extravascular lung water.

Extravascular lung water (idQw1) is measured in vivo from the difference in mean transit times, computed by extrapolating the dilution curves, of two indicators, one freely diffusible, the other confined to the intravascular space. Using 3H2O it has been shown that idQw1 is smaller than the amount of extravascular water obtained from the difference between wet and dry lung weight (Qw1). Extrapolation allows one to use dilution curves for a short time, i.e., up to onset of obvious recirculation. Clearing the dilution curves or recirculation by deconvolution extends the observation time, which then becomes limited by sampling duration rather than onset of recirculation. This procedure entails recording recirculating tracers in the pulmonary artery (PA). Dilutions of tracers at input in PA and output in a systemic artery must be related to each other as continuous time functions. This is accomplished by means of a convolution integral. Deconvolution yields the frequency function of water molecule transit time in the extravascular lung space, l(t). In dogs and men, in both normal and edematous lungs, l(t) exhibits a knee and a fairly long tail. Extravascular lung water computed from l(t), idcQw1, agrees with Qw1 and correlates with data on the extravascular thermal volume of the lung and with radiographic findings of lung edema. A radiographic score of pulmonary edema may be used clinically to assess extravascular lung water in cardiac patients and in patients with adult respiratory distress syndrome.

Capillary Permeability↗
PubMed1987

Estimation of glomerular filtration rate using 99mTc-DTPA and the gamma camera.

Two methods of glomerular filtration rate estimation have been evaluated, based on the intravenous administration of 99mTc-DTPA and the measurement of renal time activity curves by means of a computer linked gamma camera. A single 20 min plasma sample was also required. These methods were designed to minimize the component of error arising from decay statistics. One method was based on using a constant fraction of the cardiac activity in lieu of a perirenal region of interest for the background correction, the other was based on deconvolution by a constrained least squares technique. The first method, based on modifying the background correction, led to poor results (residual standard deviation 18.9 ml/min when compared with the plasma clearance method). The second method, based on constrained least squares deconvolution, worked as well as previously reported methods (residual standard deviation 14.5 ml/min) and appears suitable for clinical use.

Glomerular Filtration Rate↗
PubMed1994

Quantification of two-dimensional NOE spectra via a combined linear and nonlinear least-squares fit.

Determining the volumes of peaks in 2D NMR spectra can be prohibitively difficult in cases of overlapping, broad lines. Deconvolution and parameter estimation can be attempted on either the time-domain or the frequency-domain data. We present a method of estimating spectral parameters from frequency-domain data, using a combination of Lorentzian and Gaussian lineshapes for reference lines. This approach combines a previously published method of projecting the data on a linear space spanned by reference lines with a nonlinear least-squares fitting algorithm. Comparison of this method with other published methods of frequency-domain deconvolution shows that it is both more precise and more accurate when estimating 2D volumes.

Algorithms↗
PubMed1985

In vitro--in vivo correlation of dissolution, a time scaling problem? Transformation of in vitro results to the in vivo situation, using theophylline as a practical example.

Two principal approaches to demonstrating the continuous in vivo relevance of an in vitro dissolution test are outlined. The first uses the convolution technique to predict the concentration-time course in vivo; the second uses deconvolution as a mathematical tool to estimate the in vivo dissolution profile. The weighting function must be known to utilise either technique. Defined by the aim of the analysis the dose-normalized response to the oral solution is regarded as the weighting function (Impulse Response). In both cases the essential step is continuous comparison of the predicted time dependent data with actual readings of the same class. To permit the prediction of concentration-time data from in vitro dissolution data the basic equations for the transformation of the time base from in vitro to in vivo conditions are developed. The transformation is essential, since one cannot assume that the time scales for the in vitro and the in vivo experiment are definitely the same. The estimated in vivo dissolution profile using the deconvolution technique gives a hypothetical image of the true in vivo dissolution curve. Comparison with in vitro dissolution test results, using one of the equivalence testing procedures, reveals how closely and for how long the in vitro dissolution test simulates the in vivo dissolution process. For the formulation of theophylline studied, equivalence of the in vitro and the estimated in vivo dissolution profiles was not confirmed for the entire period of observation, but it was demonstrated for approximately the first 5 h. The later inequivalence is not due to possible non-linear or time-dependent kinetics of theophylline. There is a discussion of whether a change in pH, agitation of the formulation, diffusion conditions or the absorption rate constant along the gastrointestinal tract might explain the biphasic linear correlation of the in vitro and in vivo data observed.

Adult↗
PubMed1991

Conformational changes of recombinant human granulocyte-colony stimulating factor induced by pH and guanidine hydrochloride.

Fluorescence and circular dichroism were used to follow the pH-dependent conformational changes of granulocyte colony stimulating factor (G-CSF). Tryptophan fluorescence of the spectra monitored at 344 nm, or after deconvolution of the emission spectra, at 345 nm, showed a decrease in intensity on going from pH 7 to 4, with a midtransition pH of 5.8. On the other hand, tyrosine fluorescence measured either by the ratio of intensity at 308 nm to that at 344 nm, or by the fluorescence intensity at 303 nm after deconvolution of the spectra, increased in intensity as the pH was changed from 6 to 2.5, with a midtransition pH of 4.5. Near UV circular dichroic spectra also showed changes between pH 7.5 and 4.5, which correlated with the transition monitored by the tryptophan fluorescence. The guanidine hydrochloride-induced conformational changes of G-CSF at five pH values from 2.5 to 7.5 were also studied. Circular dichroic and fluorescence spectra revealed minor conformational changes by the addition of 1 or 2 M guanidine HCl at all pH values examined, while the major conformational transition occurred between 2 and 4 M guanidine hydrochloride. The secondary structure of the protein was most stable between pH 3.3 and 4.5. The guanidine HCl-induced denaturation of G-CSF involved more than a two-state transition, with detectable intermediate(s) present, and the structure of the intermediate(s) appeared to depend on the pH used. These results are consistent with the pH dependence of the structure described above, and demonstrate the complex conformational properties of G-CSF.

Circular Dichroism↗
PubMed1991

Stepwise determination of multicompartment disposition and absorption parameters from extravascular concentration-time data. Application to mesoridazine, flurbiprofen, flunarizine, labetalol, and diazepam.

When disposition is monoexponential, extravascular concentration-time (C, t) data yield both disposition and absorption parameters, the latter via the Wagner-Nelson method or deconvolution which are equivalent. Classically, when disposition is multiexponential, disposition parameters are obtained from intravenous administration and absorption data are obtained from extravascular C, t data via the Loo-Riegelman or Exact Loo-Riegelman methods or via deconvolution. Thus, in multiexponential disposition one assumes no intrasubject variation in disposition, a hypothesis that has not been proven for most drugs. Based on the classical two- and three-compartment open models with central compartment elimination, and using postabsorptive extravascular C, t data only, we have developed four equations to estimate k10 when disposition is biexponential and two other equations to estimate k10 when disposition is triexponential. The other disposition rate constants are readily obtained without intravenous data. We have analyzed extravascular data of flurbiprofen (12 sets), mesoridazine (20 sets), flunarizine (5 sets), labetalol (9 sets), and diazepam (4 sets). In the case of diazepam intravenous C, t data were also available for analysis. After disposition parameters had been estimated from the extravascular data the Exact Loo-Riegelman method with the Proost modification was applied to the absorptive extravascular data to obtain AT/VP as a function of time. These latter data for each subject and each drug studied were found to be fitted by a function indicating either simple first-order absorption, two consecutive first-order processes, or zero-order absorption. After absorption and disposition parameters had been estimated, for each set of extravascular data analyzed, a reconstruction trend line through the original C, t data was made. The new methods allow testing of the hypothesis of constancy of disposition with any given drug. There is also a need for new methods of analysis since the majority of drugs have no marketed intravenous formulation, hence the classical methods cannot be applied.

Algorithms↗
PubMed1994

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 weighing 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.

Animals↗