H. M. von Hattingberg

A rotating iterative procedure (RIP) for estimating hybrid constants in multi-compartment analysis on desk computers.

SummaryTherotatingiterativeprocedure (RIP) is a programming concept for non-linear least squares fitting of multiexponential equations to experimental data in pharmacokinetics. The method is economical in its use of program and active register capacity and can be employed in modern electronic desk-top computers. The algorithms necessary for obtaining primary estimates of various logarithmic components and their subsequent correction are presented, with as little higher mathematics as appeared permissible. The procedure is described in the sequence that would actually be followed in a pharmacokinetic analysis, and an example is included, as well as a skeleton version of a program written in BASIC. Some instructions for obtaining overall statistical parameters are given.

Die Pharmakokinetik endogener Substanzen

The elimination of foreign substances is subject to rules which allow a mathematical interpretation of the course of the concentration. The results yield data on the rate of elimination and the distribution volume and make it possible to estimate the dosage and the intervals of dosage; this information can therefore be used for the characterisation of drugs. On the other hand, suitable test substances are used to estimate the size of fluid spaces and the excretory efficiency of organs and organ systems.Endogenous substances are subject to the same rules. The excess curve after intravenous administration allows a similar interpretation. Apart from data on the distribution volume and the rate of elimination, it yields information on the easily exchangeable pool and on endogenous transfer.Model tests and comparative tests using the tracer technique demonstrate that the data obtained by this method agree with the true value of the transfer.Three examples emphasize the importance of the examination of endogenous substances with pharmaco-kinetic methods: jaundice (bilirubin), anaemia (iron), and hypoglycemia (glucose).ZusammenfassungDie Elimination körperfremder Substanzen folgt gewissen Gesetzmäßigkeiten, die es erlauben, Konzentrationsverlaufskurven z. B. nach rascher intravenöser Injektion derartiger Stoffe mathematisch auszuwerten. Es werden Daten über die Eliminationsgeschwindigkeit und über die Verteilung erhalten. Sie dienen zur Berechnung von Dosierung und Dosierungsintervallen und gehören damit zur Charakterisierung von Arzneimitteln. Andererseits wird mit bekannten Teststoffen die Größe von Flüssigkeitsräumen oder die exkretorische Leistungs-fähigkeit von Organen oder von Organsystemen bestimmt.Die gleichen Gesetzmäßigkeiten gelten auch für endogene Substanzen. Nach intravenöser Belastung ist die Kurve der Erhöhung über den Nüchternwert in gleicher Weise der Auswertung zugänglich. Sie liefert neben den Daten über das Verteilungsvolumen und die Eliminationsgeschwindigkeit noch Angaben über den leicht austauschbaren Pool, und über den endogenen Umsatz (Transfer).Modellversuche und vergleichende Untersuchungen mit der Tracertechnik beweisen die Übereinstimmung der mit dieser Methode ermittelten Daten mit den tatsächlichen Umsatzgrößen.Drei Beispiele sollen die Bedeutung der Untersuchung endogener Substanzen mit pharmakokinetischen Methoden darstellen: Ikterus (Bilirubin), Anämie (Eisen) und Hypoglykämie (Glucose).

High performance liquid chromatographic determination of moxalactam in human plasma and cerebrospinal fluid

SummaryA sensitive and reproducible method for the measurement of moxalactam in plasma and cerebrospinal fluid is described. Plasma proteins were removed by precipitation with ice-cold methanol at pH 5.6 and centrifugation. The supernatant was analysed by HPLC on a µ-Bondapack/phenyl column, with a mobile phase of acetonitrile/water/PIC Reagent A (20/80/1), and detection at 280 nm. The calibration curve was linear for plasma concentrations from 10 µg/ml to 60 µg/ml. Reproducibility was 4.7% (coefficient of variation) for within-day analysis and 13.8% for day-to-day analysis. Plasma concentrations in 9 moxalactam-treated patients with severe infections ranged from 0.9 µg/ml to 409 µg/ml. Individual pharmacokinetic parameters were calculated using a personal computer. In selected cases moxalactam concentrations were also determined in cerebrospinal fluid and tracheal aspirates.

A program for the simulation of multiple dosage regimens on an analog computer

SummarySmall general purpose analog computers are not usually equipped for iterative computation. Since multiple dosage problems are often encountered in pharmacokinetic studies an approximating program is proposed for rapid estimation and curve fitting. The program produces an input function simulating a staircase by integration only of the positive differentials of a sequence of rectangular impulses. The program is used to compute the maximum and minimum concentration factors of Sparteine and Quinidine as examples of two substances obeying first order kinetics. It is apparent from the results that the choice of dosage schedules is restricted both by the pharmacological and the pharmacokinetic properties of the drugs.

Pharmacokinetics of endogenous substances

In clinical pharmacokinetics the one-compartment model is of greater importance than in theoretical pharmacology since in humans only one compartment, the blood, is mostly accessible. By the single-injection technique basic parameters of the kinetics of a new drug become available, furthermore it furnishes informations on several metabolic functions and in some cases on specific organ functions if however, known substances are used. It is shown by formalistic derivation that the theory of the single-injection technique is not restricted to drugs only. The basic data, i. e. elimination constant and distribution volume, may be obtained for a substance that exists in the blood as well, provided that the blood level of this substance can be assumed to remain constant during the time of the trial, had no loading taken place. This assumption can be held true for most endogenous metabolites. It is thus possible to define the miscible pool as the amount present within the one compartment that is ready to be transferred to one or several other compartments according to the elimination constant. The product of the pool and the elimination constant, the transfer, represents therefore the amount not only eliminated from the blood but also introduced into it during unity of time, because of the constancy of the preexisting level. Hence, the transfer is a measure of the metabolism of this substance, but it is also a measure of all processes which would lead to an increase of the blood level had elimination not taken place. The activity of all eliminating processes is described by the elimination constant. The steady state of endogenous substances is thus the result of a linear invasion into the distribution volume and a concentration-dependent elimination. Both can now be analysed separately. Experimental evidence and clinical significance are proposed to sustain this concept.

Pharmakokinetische Analyse der Fluktuation im Blutspiegelverlauf während oraler Therapie mit β-Methyl-Digoxin bei Herzinsuffizienz im Kindesalter

Bei 5 herzinsuffizienten Kindern wurden die Digoxinblutspiegel vom ersten Tag der Digitalisierung an bei mittelschneller Sattigung uber eine Woche beobachtet (5 Blutproben pro Tag). Die Bestimmung der Serumspiegel erfolgte mittels eines industriellen Radioimmunassay. Mit einem selbstentwik-kelten Rechenprogramm fur Tischrechner wurden die Kurven simultan uber den gesamten Zeitraum ange-past, so das die erheblichen Fluktuationen im Blutspiegelverlauf dargestellt werden konnten. Die so ange-pasten Kurven wurden auch pharmakokinetisch analysiert. Die gewonnenen Daten korrelierten gut mit Literaturberichten. Die totale Clearance lag deutlich uber Werten von Erwachsenen. Ebenfalls berechnet und graphisch dargestellt wurde die Menge an Digoxin im Gesamtorganismus, die weniger ausgepragte Fluktuationen aufwies, aber wahrend der ersten Tage der mittelschnellen Sattigung deutlich uber der wahrend der Erhaltungsphase lag.

Use of Analogue Computers in Pharmacokinetics

The development of computer technology in recent years has brought substantial advantages to almost every field of science. Where detailed observations can be analysed automatically, the investigator has more time to plan and carry out experiments. Experimental results can now be analysed mathematically by computer where they would have been a great burden to a biological scientist with no special training in mathematics. The use of computers has not only lightened our work-load, however; it has also enhanced our knowledge of laws and relationships in nature and has opened up new methods and areas of work which can then be thoroughly investigated by the classic experimental procedures. However, the lightening of the work-load in data processing is more than out-weighed by the new tasks to which it gives rise.

Practical Application of Pharmacokinetic Procedures

The aim of this chapter is to review some methods used in human and animal experiments in the course of the development of new drugs. Most of the examples relate to antibacterial chemotherapy, although the proce-dures described are not restricted to this group of drugs. The methods presented here have been confirmed in our own studies.

Volume of Distribution

Every load with a drug, test substance or other material foreign to the body disturbs the natural steady state. The foreign substance enters the body by absorption from the gastrointestinal tract or an intramuscular or subcutaneous depot, by intravenous administration, or by some other route. In each case the substance appears in the blood, which simply acts as the organ of transport, although the lymph is sometimes an intermediate transport organ as well. The further distribution of the substance into other spaces is largely due to simple diffusion.

Praktische Anwendung pharmakokinetischer Verfahren

In diesem Kapitel sollen kurz diejenigen Methoden besprochen werden, die im Tier- und Humanversuch vor allem dann angewendet werden, wenn es sich um die Entwicklung neuer Praparate handelt. In diesem Zusammenhang sind in erster Linie die Gegebenheiten der antibakteriellen Chemotherapie berucksichtigt, doch ist der Anwendungsbereich der Verfahren nicht hierauf beschrankt. Es wurden hierbei diejenigen Methoden dargestellt, die sich in eigenen Versuchen bewahrt haben.