Drug Metabolism Methodology

Throughout the history of drug metabolism, advances in our understanding have coincided with advances in analytical technology. The earliest metabolism studies of Wöhler, Baumann, Jaffe, and others were limited by the need to isolate new compounds and deduce their structures mainly from elemental analysis and derivatization. The ability to separate compounds depended on wide variations in chemical and physical properties.

A pioneer in the development of separation techniques—and thereby drug metabolism—was Bernard B. Brodie. After an undistinguished high school career, Brodie made his mark in the Royal Canadian Signal Corps, where he became a boxing champion in his weight class. With money won playing poker in the army, Brodie enrolled in McGill University. It wasn’t until his fourth year at McGill that Brodie's interest in science was stimulated by his work on an experimental project for chemistry professor W.H. Hatcher.

Thus inspired, Brodie went on to obtain a degree in organic chemistry at New York University, where he studied the distribution of thiocynate and iodide under varying physiological conditions— studies requiring development of new methods of analysis to solve the problems at hand. During his stay at NYU, Brodie was influenced by two eminent pharmacologists— B. Wallace and Otto Loewi.

As part of James Shannon's team at NYU’s Goldwater Research Service, Brodie applied his training to solving problems in pharmacology. The team's mission in 1941: a more effective anti-malarial therapy. Although atabrine seemed to have the potency required, an effective non-toxic dosing regimen had proven evasive. Analysis of atabrine was complicated by the presence of metabolites. Brodie helped develop methodology to separate parent from metabolites and found that arabrine initially concentrated in liver and muscle. With this information, the team developed a loading dose regimen yielding effective plasma levels for the desired length of time.

Brodie’s separations and detection techniques and his approach of applying novel analytical methodology to difficult pharmacological problems has served metabolism scientists well. As head of the Laboratory for Clinical Pharmacology at NIH, he influenced others who became leaders in metabolism science.