Biomedical subjects
Publications and source records attributed to P Veng-Pedersen.
Part I of this article, which appeared in the previous issue of the Journal, covered the following topics: fundamental definitions, general mean time parameter relationships and mean time parameters of classical compartmental systems. It also offered a number of examples to clarify and illustrate the various concepts.
System approaches mathematically describe a general property of a pharmacokinetic system without modeling in specific terms the kinetic processes responsible for the general property considered. Definitions, basic concepts, kinetic basis, and rationale for system approaches as well as advantages and disadvantages of system approaches are presented and discussed. It appears that the system approaches may offer certain advantages over more traditional methods for many practical applications.
Pharmacokinetic system approaches mathematically describe a general property of a pharmacokinetic system without modeling in specific terms the kinetic processes responsible for the general property. Certain applications of the system approach including methods for evaluating drug delivery, drug distribution, drug secretion, and biotransformation in linear and nonlinear pharmacokinetics are presented and discussed. Linear system formulae for various mean time disposition parameters and a disposition decomposition-recomposition system approach for predicting drug levels when the drug clearance changes are presented and discussed. System approaches offer certain advantages over traditional approaches for many practical applications.
A general theoretical framework is constructed for the relationship between a pharmacokinetic response r (e.g., systemic drug concentration or input rate), and an observed pharmacologic effect response E. The overall relationship may be described mathematically by E = omega(r) = omega p(omega b(omega r(r))) where omega is an operator that describes the overall relationship, and omega r, omega b, and omega p are operators that describe the contributions of components of the pharmacodynamic system. The kinetic basis for applying certain general mathematical properties such as linearity are discussed. The result is the introduction of various specific mathematical structures that may be applied to pharmacodynamic systems [e.g., E = phi t(r), E = phi t(psi r*r), E = phi p(psi p*phi b(r)), and E = phi p(psi p*phi b(psi r*r))].
A system approach to the analysis of pharmacodynamic systems is applied to the relationship between the glyburide serum concentration (Cd) and a resulting pharmacologic effect response, that is, the C-peptide serum concentration (Cc) in patients with non-insulin dependent diabetes mellitus (NIDDM). Glyburide, glucose, and C-peptide serum concentrations were measured in eight patients with NIDDM following each of five treatments: Treatment A: one glyburide 5-mg tablet (formulation 1); Treatment B: one glyburide 5-mg tablet (formulation 2); Treatment C: glyburide solution as an intragastric infusion (4.67 mg over 12 h); Treatment D: glyburide solution as an intragastric infusion (9.33 mg over 12 h); and Treatment E: no glyburide. The overall relationship between the C-peptide (Cc), glyburide (Cd), and glucose (Cg) serum concentrations is successfully described by operator equations of the form, Cc(t) = t-infinity psi p(t-u)phi t(Cd(u), Cg(u)) du or Cc(t) = t-infinity psi p(t-u)phi t(Cd(u), Cg(u),u) du. The forms of the individual functions are selected empirically based on the results of the present study and those of previous investigations, and are estimated by conventional curve-fitting procedures. The resulting operator equations are used to describe glyburide pharmacodynamics in NIDDM patients and to estimate the optimal glyburide systemic concentration and delivery rate profiles for such patients based on pharmacodynamic response.
This study was undertaken to determine if a compound which alters the bulk flow of cerebrospinal fluid (CSF) alters the elimination kinetics of a compound in the CSF. Acetazolamide was chosen as the CSF bulk flow-altering agent. It produces a relatively large effect on the flow process, affecting both choroidal and extrachoroidal CSF production, and has been shown to affect CSF flow following iv administration. The compound monitored was nicotine. Acetazolamide was administered orally for one week before and intravenously during the experiment. Nicotine was administered by a bolus injection directly into the CSF via the cisterna magna. The results indicate that the introduction of acetazolamide into the general circulation increases the rate of removal of nicotine from the CSF. Subjects receiving acetazolamide had elevated CSF pressures. The increase in CSF pressure associated with the administration of acetazolamide suggests pressure as a possible factor in the observed increase in the rate of removal of nicotine.
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The description of the relationship between different responses measured simultaneously in the same subject is commonly described in terms of specific pharmacokinetic models such as linear compartmental models. An alternative system approach involving response mapping operators (RMOs) is presented. The theoretical and mathematical basis of the RMO approach are derived. The assumptions, limitations, and practical significance of the RMO approach are discussed. The derivation of the RMO is illustrated with several examples. An algorithm and computer program for implementing the RMO in a routine manner is presented. The usage of the computer programs RMO and MAP presented are demonstrated using the pharmacokinetics of trimazosin and cefamandole in humans as examples. The RMO approach offers a new and powerful tool in pharmacokinetic analysis, which allows the investigator to approach certain problems in an objective, rational way without getting involved in specific pharmacokinetic modeling.
System approaches in pharmacokinetics are defined as generalizing and simplifying modeling approaches that mathematically model a general property of the pharmacokinetic system without modeling specifically the individual kinetic processes responsible for the general property considered. The rationale for the use of system approaches is discussed and the kinetic basis of some of the approaches is presented. An overview of the approaches is presented together with a comparison to classical approaches involving specific pharmacokinetic models. Examples are given from different application areas involving problems in linear and nonlinear pharmacokinetics and in pharmacodynamics. The advantages, disadvantages, and limitations of the system approaches are discussed. In several application areas the system approach offers some rational methods and procedures with distinct advantages over more traditional approaches.
Adsorption of phenobarbital from simulated intestinal and gastric fluids by two activated charcoals was studied. Adsorption isotherm data were analyzed by the linearized Langmuir equation and by nonlinear least-squares regression employing both Langmuir and Freundlich models. These analyses indicated differences in the capacities of the two charcoals for phenobarbital which could not be completely explained by surface-area considerations.
Ten- and 12-h workdays are relatively common in the chemical and other non-labor intensive industries both in the United States and Europe. Based on pharmacokinetic principles, persons who work 10-12 h shifts and are exposed to chemicals with a terminal half-life between 5 and 200 h will absorb a larger quantity of the toxicant or have higher peak blood levels than persons who work 8-h shifts. To evaluate the effects of exposure duration and repeated exposure on the elimination of carbon tetrachloride (CCl4), rats were repeatedly exposed to 100 ppm 14CCl4 for either 8 or 11.5h/day. Pharmacokinetic equations which describe the plasma concentration and pulmonary elimination during and following single and repeated inhalation exposures were developed. These equations are based on a diffusional type of input function and a linear systems analysis approach. They can be used to make predictions of the cumulation of toxicant following repeated exposure, the relative change in the plasma level following multiple exposures, and the steady-state plasma level based only on the elimination of the chemical in the breath. The pharmacokinetic analysis indicated that rats repeatedly exposed to 100 ppm CCl4 for 11.5 h/day for 4 days per week, or 8 h/day for 5 days per week, will not have increasing plasma levels. The analysis also predicted no significant difference in the peak plasma concentration of CCl4 between the 8 and 11.5h/day schedules following either 1 or 2 weeks of exposure. Due to rapid pulmonary elimination by the rat, the steady state plasma level of CCl4 was reached after only three consecutive exposures for both schedules. The alpha and beta half-lives (X +/- SE) of pulmonary elimination for the 8 h/day group were 84 +/- 9 min and 400 +/- 32 min, respectively. The half-lives for the 11.5 h group were 91 +/- 6 min and 496 +/- 32 min, indicating that the beta phase half-life was significantly longer than that of the 8-h group. This observation, coupled with the tissue distribution data (Paustenbach et al. 1986), suggests that during the longer exposure period a greater fraction of CCl4 is placed in the poorly perfused tissues like fat, thus altering the time-course of elimination in the breath. A general formula for adjusting TLVs for unusually long work schedules is also developed and presented.
Disposition decomposition analysis (DDA) is applied to evaluate the rate and extent of drug delivery from the sampling compartment to the peripheral system, i.e., peripheral bioavailability. Four parameters are introduced which are useful in quantifying peripheral bioavailability. The compounded peripheral bioavailability, F comp, is the ratio between the total compounded amount of drug transferred to the peripheral system and the injected dose, D. The AUC peripheral bioavailability, FAUC, is the ratio between the area under the amount vs. time curves for the peripheral system and the sampling compartment. The distribution time td, is the time following an i.v. bolus at which the net transfer of drug to the peripheral system reverses in direction. The maximum peripheral bioavailability, Fmax, is the maximum fraction of an i.v. bolus dose that is present in the peripheral system at any one time. Equations are derived which permit estimation of those parameters from drug concentrations in the sampling compartment. Simple algorithms and a computer program are provided for estimating Fcomp, FAUC, td, Fmax, and other parameters relevant to DDA for drugs that exhibit a linear polyexponential bolus response. Estimates of Ecomp, FAUC, td, and Fmax are presented for several drugs.
An exact formula relating the terminal log-linear beta parameter and the drug clearance is derived. The expression is valid for drugs with a linear, polyexponential disposition kinetics. The formula is useful for calculating the clearance when the clearance has changed between drug administrations and requires only drug level data from the terminal, log-linear elimination phase in addition to data from a single separate i.v. administration in the same subject. Data from an i.v. administration are necessary in order to apply the disposition decomposition technique to isolate and uniquely define the distribution kinetics in terms of the distribution function h(t). The different clearances can then be calculated from the beta values of the log-linear terminal drug level data and the parameters of h(t). The theoretical basis of the method and its assumptions and limitations are discussed and various pertinent theorems are presented. A computer program enabling an easy implementation of the proposed method is also presented. The mathematical and computational procedures of the method are demonstrated using kinetic data from i.v. and oral administrations of cimetidine, diazepam, and pentobarbital in human subjects. The classical V.beta method of approximating the clearance as the product of volume of distribution and beta is considered for comparison. For the three drugs considered the V.beta method which assumes a single exponential disposition kinetics leads to excessive errors when applied in absolute clearance comparisons. However, when applied in relative comparisons in the form of the "beta correction" the errors cancel out to some extent depending on the magnitude of the distribution kinetic effect. Whenever possible it is advisable to apply the proposed method to avoid such errors.
During 20 weeks of aurothioglucose therapy, gold in a mother's serum and breast milk and her nursing infant's serum and urine were measured. The mother's steady state plasma gold was 4.05 mg/l; it was 0.041 mg/l in breast milk. Only 0.0255 mg gold appeared in the breast milk/24 h. We calculated that only 0.1785 mg gold (0.71% of the weekly dose) would appear in the breast milk over a week. No gold (less than 5 X 10(-7) mg/l) was found in the infant's plasma or urine. It is very unlikely that more than minute amounts of gold are absorbed from the mother's breast milk when breast feeding an infant.
A method is presented which enables an explicit evaluation of the relative rate and extent of drug absorption of drug products using an oral drug solution as a reference, thereby avoiding the need for intravenous administration of the drug. The method is demonstrated using data from two sustained release phenylpropanolamine preparations and an oral solution of this drug in a human subject.
A method is presented which enables the rate and extent of gastrointestinal release to be evaluated at steady state. The method requires a solution of the drug to be given orally as a reference in the same subject receiving the test product. The special mathematical and numerical aspect of the method is discussed. The method which makes use of the previously published deconvolution computer program DCON is demonstrated by evaluating the gastrointestinal release of a theophylline sustained release product at steady state.
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The single pass mean residence time in peripheral tissues, tp1, is a characteristic constant of linear pharmacokinetic systems and nonlinear systems with linear distribution kinetics. It is descriptive of distribution kinetics in such systems and is not dependent on elimination kinetics as are other related parameters, e.g., mean residence time in peripheral tissues, tp. Equations are derived which permit estimation of tp1 from experimental data for systems in which no peripheral elimination occurs. The type of data required are systemic drug levels resulting from iv administration. The probability density function for single pass residence time in peripheral tissues is derived. It is shown that tp1 is related to the amount of drug in the peripheral tissues at steady state according to (Ap)ss = CLdCsstp1, where CLd is the distribution clearance, and Css is the steady-state systemic drug level. Values of tp1 are presented for several drugs.