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Application of Stable Labelled Drugs in Clinical Pharmacokinetic Investigations

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Summary

The application of stable isotope labelled drugs in clinical pharmacokinetic studies has rapidly increased over the past decade. Isotopes are atoms of the same chemical element, but differ from one another by their mass, due to the different number of neutrons in the nucleus. As they are not radioactive they can be administered in therapeutic doses to man. The major applications of stable isotope labelled drugs are as an internal standard in gas chromatography-mass spectrometry (GC-MS) analysis and as so-called ‘biological internal standards’. This latter application is accomplished by administering the stable isotope labelled drug to man, measuring its plasma concentration and determining various pharmacokinetic parameters.

Problems associated with this technique include having a suitable mass difference between labelled and unlabelled drug, having the label in the fragment ion to be monitored and exclusion of isotope effects.

The applications of the technique include investigations into the pharmacokinetics and autoinduction of carbamazepine metabolism in epileptic patients during long term monotherapy and combination therapy, and determination of the time course of carbamazepine disposition in children, studies of valproic acid pharmacokinetics during combined anticonvulsant therapy and during pregnancy, and the influence of valproic acid on phenobar-bitone (phenobarbital) disposition. These studies have been conducted in patients by substituting the normal dose with a pulse dose of the labelled antiepileptic drug and hence normal therapy was continued and not withdrawn. Also, several studies have been conducted with a solution of stable labelled verapamil, including single dose and multiple dose pharmacokinetics, and disposition and bioavailability in liver cirrhosis and in a patient before and after construction of a mesocaval shunt.

Aspects of drug metabolism have also been studied by the use of stable isotopes. These include the metabolism of procainamide and N-acetylprocainamide. Stereoselectivity of drug metabolism has been investigated using a pseudoracemate of warfarin, and the interaction of the enantiomers of warfarin with phenylbutazone and with quinalbarbitone (secobarbital) has elegantly demonstrated this stereoselectivity of human drug metabolism. Absolute bioavailability studies with N-acetylprocainamide, barbitone and verapamil have been performed with stable isotopes in that both the intravenous and oral doses were given simultaneously to man. The advantage of this technique has been clearly demonstrated in a study on the relative bioavailability of 2 different Imipramine formulations, in which it was shown that to detect a 20% difference in area under the plasma concentration-time curve (with a probability of 0.8) between the 2 formulations required the use of 20 subjects, but only 3 to 4 subjects with the stable isotope method. Other studies on the relative bioavailability of different formulations have been conducted with maprotiline, verapamil and timolol. The influence of formulation factors on the absorption of benoxaprofen, dextropropoxyphene and methoxsalen have been conducted by using solutions of their stable isotopes.

The major advantages of using stable isotope labelled drugs are: (a) that time-dependent (i.e. day-to-day) variations in drug disposition are minimised; (b) a small number of subjects are required in bioavailability studies; and (c) patients are less inconvenienced, for studies which normally require dosing on 2 occasions can now be easily accomplished on the 1 occasion.

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Authors and Affiliations

  1. Department of Medicine, University of Bonn, Bonn, Germany

    Michel Eichelbaum, Gerd E. von Unruh &  Andrew Somogyi

  2. Department of Clinical and Experimental Pharmacology, University of Adelaide, GPO Box 498, Adelaide, South Australia, 5001, Australia

    Michel Eichelbaum, Gerd E. von Unruh &  Andrew Somogyi

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  1. Michel Eichelbaum
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  2. Gerd E. von Unruh
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  3. Andrew Somogyi
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Eichelbaum, M., von Unruh, G.E. & Somogyi, A. Application of Stable Labelled Drugs in Clinical Pharmacokinetic Investigations. Clin Pharmacokinet 7, 490–507 (1982). https://doi.org/10.2165/00003088-198207060-00002

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