Tritium-labeled drugs

Pentazocine has been successfully used to relieve labour pain [201] and its obstetric use in place of pethidine is favoured by,its apparent inferior ability to pass the placental barrier [206]. A clinical trial of (+)- and (-)-pentazocine adds to the rare number of examples in which optical enantiomorphs have been evaluated [207]. In post-operative patients, response to 60 mg of the dextro isomer was less than that to 5 mg of morphine, while 25—29 mg of (-)-pentazocine was as effective as 10 mg of morphine. Hence most of the activity of the race-mate resides in the laevo isomer, as anticipated from results in animals [208]. Several studies of the distribution, excretion and metabolism of pentazocine have been made. Peak levels of the tritium-labelled drug (and its c/s-3-chloroallyl analogue) were present in the C.N.S. of a cat within 40 minutes of intramuscular administration [209], the comparable figure for morphine being 2 hours [210]. 

The clinical pharmacology of both digoxin and digitoxin have been extensively investigated using tritium-labeled drugs (B14, D8, Dll, M5, M6, R3) in patients and human volunteers they exhibit several important differences. 

On the other hand, the detection efficiency for tritium during whole-body autoradiography is only about one-fiftieth that of the two more energetic isotopes, so, if such studies are anticipated, even more tritium-labeled drug would have to be prepared. 

Tritium-labelled 7V-(4-phenylphenacyl)heliotridanium bromide (55) has been prepared. The absorption, tissue distribution, and excretion of this radioactive antispasmodic drug in rats were then studied.84... 

The nature of our concern is best illustrated by a specific example. Blank and Kidwell use a cocaine solution of 100,000 ng/mL for their contamination experiments, to which they add approximately 1 pCi of tritium-labeled cocaine, i.e., approximately one million counts per minute. Therefore, they have approximately a sensitivity of 10 cpm/ng of sample. Decontamination of hair means that residual drug concentration must drop below the endogenous cutoff level of 5 ng/10 mg of hair, i.e., to 50 cpm/10 mg hair. Now if the labeled cocaine has a radiochemical impurity of as little as 0.1%, this corresponds to 1000 cpm or to 100 ng of residual cocaine equivalents. Since self-irradiation of tritium-labeled material tends to form polymeric impurities, and since these are likely to preferentially bind to hair, one incurs a major risk of concluding erroneously that the residual radioactivity represents residual cocaine contamination rather than contamination by polymeric degradation products. 

Radioactivity, however, is still a very sensitive means of measuring the presence or absence of a given material. Assay methodology has now come full circle, to the development of an ultrasensitive enzyme RIA. In this technique, an antigen is bound to a solid phase. Antibody will bind to the antigen, which could be a drug-protein conjugate, and the presence of bound antibody is detected by means of a second antibody coupled to alkaline phosphatase. So far this is the standard enzyme-linked immunosorbent assay (ELISA). However, if the substrate is tritium-labeled adenosine monophosphate, it is converted by the enzyme to tritium-labeled adenosine, which may be readily separated and measured. The detection limit for this assay for cholera toxin is approximately 600 molecules of the toxin (22). 

Calcium channel antagonist drugs are a relatively new class of therapeutic agents, all of which influence the binding of tritium-labeled nitrendipine to receptor sites. Many of these drugs are not asymmetric but others, such as verapamil, are. RRA are available for these compounds (65,66). 

A second software feature capitalizes on the fact that many potential drug candidates contain atoms that are not naturally occurring in the body and which possess unique isotopic patterns. In particular, chlorine and bromine atoms give unique and distinctive mass spectral signals. The computer can evaluate the sample dataset and find any chromatographic peaks that contain these characteristic isotopic patterns. An example of how these software routines can simplify a complex chromatogram is shown in Fig. 2. This compound contained a tritium label, so the top trace (A) shows peaks corresponding to radioactive metabolites. The second... 

Samuel K, Yin W, Stearns RA, Tang YS, Chaudhary AG, Jewell JP, et al. Addressing the metabolic activation potential of new leads in drug discovery a case study using ion trap mass spectrometry and tritium labeling techniques. J Mass Spectrom 2003 38 211-21. 

---