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The Place of Mass Spectrometry in Drug Metabolism Studies
Abstract
A vast fund of published information on the use of mass spectrometry and associated techniques for the study of drug metabolism has accumulated in recent years. The annual “Specialist Periodical Reports” on mass spectrometry of the London Chemical Society is particularly worthy of mention. This publication reviews all the literature in the field. In the issue covering the two year period from 1972 to 1974 (1), there are more than one hundred and forty reviews of papers devoted to mass spectrometry applications for drug metabolism. From 1974 to 1976 (2), there were a hundred and twenty.
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When a dose of drug is administered, three main phases of drug action may be distingushed. In the "pharmaceutical" phase the dosage form disintegrates, the active substance dissolves and becomes available for absorption. The second phase ("pharmaco kinetic" phase) includes absorption, distribution, metabolism, and excretion. That fraction of the dose which finally reaches the circulation after absorption will be available for biological action in the third, or "pharmacodynamic" phase when the drug reaches the target tissues and a drug-receptor interaction takes place. The objectives in studies of drug metabolism are: (a) to identify the pathways by which drugs are transformed in the body; (b) to ascertain quantitatively the importance of each pathway and intermediate; (c) to identify and quantify endogenous constituents influenced by the drug or its metabolites which may interfere with common metabolic processes. Since metabolites usually differ from their precursors by only a single chemical group, the resulting metabolic pathways generally consist of a series of closely related compounds. Mass spectrometry is uniquely suited for the analysis of drugs and metabolites for several reasons: only a minimal amount of sample preparation is needed, closely related compounds can be analyzed in a single step, structures can often be deduced directly from the mass spectra without the need for pure reference spectra, and constituents can be quantified with relative ease even when present in fractional nanogram quantity.
Critical flicker frequency (CFF) is a neurophysiological variable which can be measured precisely and which shows little diurnal fluctuation. In a double blind cross-over study on six male volunteers, hydroxyzine hydrochloride 25 mg caused sedation that was recognised subjectively. It was also assessed quantitatively by changes in CFF in which the effect of hydroxyzine appeared after the second hour, persisted during the third and fourth hours, but had disappeared after the seventh hour.
The compiled papers offer a wide variety of examples illustrating the potential applications of mass spectrometry in biochemistry and medicine. Abstracts were prepared for selected papers. (JSR)
"Consists of the proceedings of the 4th-5th International Symposium on Mass Spectrometry in Biochemistry and Medicine" Symposium organized by the Italian Group for Mass Spectrometry in Biochemistry and Medicine
Gas chromatograph/mass spectrometer/computer systems can be used to quantify a wide variety of compounds of clinical interest. A quadrupole instrument operated in the chemical ionization (Cl) mode was used in these studies. Because of the sensitivity and specificity of selective ion detection, it is possible to make measurements routinely in the nanogram to picogram range, with 0.1-1.0 ml samples of plasma and 1-5 ml samples or urine. Internal standards, preferably stable-isotope-labeled compounds, were added to the biological samples before isolation was begun. We describe clinical applications of these procedures to problems in toxicology, pharmacokinetics, and perinatal pharmacology.
Pharmacokinetic studies involving plasma, urine, breast milk, saliva and liver homogenates have been carried out by selective ion detection with a gas chromatographic-mass spectrometric-computer system operated in the chemical ionization mode. Stable isotope labeled drugs were used as internal standards for quantification. The half-lives, the concentration at zero time, the slope (regression coefficient), the maximum velocity of the reaction and the apparent Michaelis constant of the reaction were determined by regression analysis, and also by graphic means.
Progress in Drug Metabolism
- B J Millard
A Review of the Literature Published between
- R A W Johnstone
- RAW Johnstone