John Oates: A closer look  pg. 7

Putting together the pieces

Clinical pharmacology, perhaps more than other biomedical research disciplines, has an obvious link to the pharmaceutical industry, Oates says.

Indian Paintbrush: An example of Oates’ extensive collection of wildflower photos.
“To put it simply, you like for your work to be where the action is. And molecules going into human beings for pharmacologic purposes are what we’re interested in. Our cooperation with industry has repeatedly been valuable in bringing us investigational tools for discovery.”

Methyldopa was one such “tool” that allowed Oates and colleagues to illuminate aspects of blood pressure regulation. The team’s research on guanethidine, another blood pressure medication, identified drug interactions as an interesting and important area in clinical pharmacology, Oates says.

Studies of a drug candidate that never made it to market also had a major impact on concepts in drug metabolism.

The drug candidate, code named SU-13197, was being investigated as a potential antiarrhythmic drug when the global chemical company Ciba enlisted Oates’s assistance in studying its metabolism and human pharmacology.

“It was just the beginning of the era of realizing that it’s important to investigate metabolic fate early in the process of drug development,” Oates recalls.

Oates and his colleagues followed the availability of radiolabeled SU-13197, discovering that only a fraction appeared in the systemic circulation following oral administration compared to intravenous administration. It was the first solid evidence of what came to be known as “first pass metabolism”—the clearance of an orally delivered drug by the liver on the drug’s “first pass” through the body.

The team also found evidence that drugs with a high first pass metabolism, like SU-13197, had a high degree of inter-individual variation, a concept that continues to shape drug discovery and development now in the genomic era.

The late Grant R. Wilkinson, Ph.D., who joined the faculty in 1971, and Shand went on to develop what Oates describes as “elegant clearance concepts.” But that would not have happened were it not for a “very proactive” interaction with industry.

“It’s just one example of how our involvement with industry gave us the tools to make discoveries,” Oates explains. “Once we had those tools, the opportunities for creativity opened.”

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