Throughout the history of xenobiotic metabolism it is clear that advances in our understanding have been coincident with advances in analytical technology. The earliest metabolism studies of Woehler, Baumann, Jaffe, and others were limited by the need to isolate each new compound and deduce the structure mainly from elemental analysis and derivatization. The ability to separate compounds depended on wide variations in chemical and/or physical properties. One of the pioneers in the development of separation techniques and thereby significant advances in xenobiotic metabolism was Bernard B. Brodie. Brodie, who had a slow start in his academic studies, matured in the Royal Canadian Signal Corps and subsequently enrolled at McGill University. It wasn't until his fourth year at McGill when Brodie's interest in science was stimulated by his work on an experimental project guided by chemistry professor Dr. W.H.Hatcher. During long hours of observation and data collection he became enthralled with the thought of designing and executing his own scientific experiments. Thus inspired he went on to get a degree in organic chemistry at New York University where he studied the distribution of thiocyanate and iodide under varying physiological conditions. These studies required development of new methods of analysis to solve the problems at hand. During his stay at NYU Brodie was greatly influenced by two eminent pharmacologists G.B. Wallace, and the Nobel Laureate, Otto Loewi. He decided to apply his training in organic chemistry to solving problems in pharmacology.
At the start of the war in 1941, the Goldwater Research Service at NYU was directed by the renal physiologist James A. Shannnon. Shannon assembled a distinguished team, including Brodie, to accomplish their main mission -a more effective anti-malarial therapy. The war-induced shortage of quinine was putting our troops in jeopardy in foreign lands. Although atabrine seemed to have the potency required , an effective nontoxic dosing regimen was proving difficult to develop. The analysis of atabrine was complicated by the presence of metabolites. Brodie and Sydney Udenfriend developed methodology to separate parent from metabolites and used this to study the distribution of atabrine. Finding that atabrine initially concentrated in liver and muscle led to the development of a loading dose regimen that yielded effective plasma levels for the desired length of time.1
The principle of developing efficient, sensitive analytical methods to solve pharmacological problems was to stay with Brodie throughout his career. Brodie's publication of a series of 6 papers in 1947 detailed separations and detection techniques of general applicability to a wide range of organic compounds and laid the groundwork for future metabolism scientists.2
Although Brodie published nearly 400 papers his greatest contributions may have been as Head of the Laboratory for Chemical Pharmacology at NIH where he assembled a cadre of scientists who would be the leaders in drug metabolism science including Julius Axelrod, Bert LaDu, James Gillette, and many others. Even today progress in drug metabolism is driven by technology. Brodie's approach of applying novel analytical methodology to difficult pharmacological problems has served metabolism scientists well over the decades.3
Ref: 1Shannon, J.A., Earle, D.P., Brodie, B.B., Taggart, J., Berliner, R.W. J.Pharm.Exp.Ther.81:307-330(1944). 2Brodie,B.B.,Udenfriend, S., Baer, J.E., J.Biol.Chem.168:299-309(1947); Brodie, B.B.,Udenfriend, S.,Dill,W.,Downing,G.,Ibid.pp.311-318;Brodie, B.B.,Udenfriend,S., Dill,W., Chenkin, T. Ibid.pp.319-325; Brodie, B.B., Udenfriend, S., Taggart, J.V., ibid.pp.327-334; Brodie, B.B., Udenfriend, S., Dill, W., Ibid.pp.335-339; Josepheson, E.S., Udenfriend, S., Brodie, B.B., Ibid.pp.341-344. 3Costa,E.,Karczmar,A.G.and Vessell,E.S.Ann.Rev.Pharm.Tox.29:1-21(1989)
Photographs from Victoria A.Harden, Ph.D, Historian,NIH.:.Dr. B.B. Brodie from 1987 NHLBI "A Salute to the Past", NIH from "A short history of NIH" on NIH website:www.nih.gov
6/26/2017 » 6/29/2017
14th European ISSX Meeting