Labeled First Dose

Gather the most information from each patient. In the first patient, besides tolerance of a small dose, determine the metabolic routes and kinetics of the drug by using a labeled dose. Use a stable label such as deuterium and mass spectrometry to trace the metabolites or use a radioactive tracer.

Before I have taken small doses of radioactive test drugs, I have asked about the distribution and persistence of the label in two appropriate species after single doses. If the label does not accumulate in any special organ, such as eyes or testes, and if it is eliminated promptly, then I would not be concerned about any damage from the label.

If the drug is excreted in urine of several species, then my kidneys will probably eliminate it. If the drug is metabolized by a pathway defined in animals, and if I am known to have similar pathways, then the drug should not persist unduly.

This concept could be tested further by measuring the metabolism of the drug in ex-vivo preparations of human liver microsomes, or even individual human drug-metabolizing enzyme isoforms. Having identified the specific isoform that metabolizes the drug ex-vivo, I could be tested with a safe common drug to ensure that I have a normal level of activity of that specific isoform via which to eliminate the test dose promptly. My own blood could be tested ex-vivo to examine the binding of test drug and label to cells and proteins and to see if any ex-vivo transformation of the substance occurs.

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