Long before drugs reach the pharmacy shelf, Melanie Otten Manis '74 is part of a team that develops a picture of how the human body will handle those drugs.
Manis is a research scientist for the Upjohn Company in Kalamazoo, Mich., specializing in drug metabolism. In other words, she studies how the human body will absorb,
distribute, metabolize, and excrete potential new drugs. During the past nine years, she has worked on anxiolytic, antiarthritic, antiarryhythmic, and cholesterol lowering medications.
One part of her job is to select compounds for development that are metabolized slowly, so that the effect extends
for the maximum length of time and patients will have to take the drug less often. She studies drugs recently synthesized by the chemists at Upjohn and selects a fraction of them that look promising.
“Each member of the team-chemist, pharmacologist, toxicologist, and drug metabolism scientist-contributes to the selection of new compounds for development as drugs,” she says. “Our combined information from these different areas of research helps us make better choices. Due to a variety of factors, the success for new compounds is still pretty
low somewhere in the order of 1 in 5,000 to 1 in 10,000.”
She also studies the timecourse of disposition. Colestid, which lowers cholesterol levels in the body, was recently approved by the Food and Drug Administration for two new formulations, in part because of Manis's research.
In 1993, she used radiolabelled Colestid administered to dogs and human subjects to determine how long it took to excrete the drug and to demonstrate that it was not absorbed. The information was used in the application for adding the new formulations, flavored granules and tablets. “These forms of the drugs are easier to take, so patients are more likely to take the full dose needed to help control their cholesterol levels,” she says.
Manis has also been active in applying in vitro methods to studying drug metabolism. Because the liver is the main site for metabolism of drugs and contains a wide range of enzymes, she uses thin slices of liver tissue from laboratory species, adds potential new drugs to the beaker or test tube, and compares the results to studies performed in vivo in the same lab animal species. If this in vitro/in vivo correlation is good, the process can be extended to humans using the liver slice method. The test gives her a picture of how a human will metabolize a new drug prior to administration in the clinic.
“We use this information to correlate the metabolism in lab animals with that in man,” she says. ” If the metabolism in animals is similar to man, then the effects of the drug at a variety of dose levels may be as well.
“Metabolism of these foreign compounds by the body is amazing. You have to expect the unexpected in research and always be open to the new and unusual result. That's what keeps it so exciting.”
Access to human liver tissue for preparing slices enabled Manis to set up a human liver bank-a valuable resource for comparing metabolism of standard compounds to potential new drugs in humans. The results allow her to characterize the pathways the body uses to metabolize a drug and specific enzymes involved-important for the individual who is taking multiple medications. Sometimes these medications can interact because they are metabolized by the same enzyme. The interaction can cause extended pharmacological effects or adverse side effects. Manis says this detective work is fun, and the impact of the results on drug development are very satisfying.
Manis realized she was interested in science as a career at Union where
analytical chemistry and biochemistry piqued her interest. “Dr. Helen Birecka was a great example for me, both personally and professionally. The Chemistry Department was very supportive, encouraged me, and gave me the tools to succeed in graduate school,” Manis remembers.
She studied biochemistry and microbiology before getting a degree in pharmacology from Michigan State University. The Ph.d. was necessary, she says, to gain the flexibility and scientific freedom she wanted. However, no academic degree could have prepared her for the work at Upjohn. “There isn't a university training ground for the work I do,” she says. “You have to work in the industry and learn it. It's a marriage between biochemistry and animal physiology with medicinal chemistry and kinetics.”
In a sense, Manis hasn't gone far from the upstate New York dairy farm where she grew up. She, her husband, and their two young daughters, Rebecka, five, and Sarah, twenty-two months, live on a 150-acre farm outside of Kalamazoo, where her husband raises wheat and corn.
After giving birth to her second daughter, Manis recently returned to work on a part-time basis. “Upjohn
has been very open to changes in my work schedule and has offered me projects that can be done on a part-time basis,” she says. “Right now I am focused on just one aspect of the research scientist's job-writing regulatory documents. As a part-time employee, I have also done development projects involving lab work. Flexibility is key, for both management and employee. The more open one is to change, the more opportunities there are.”
The flexible work schedule has allowed her to achieve a balance in her life between family and career. Now, if she wants to, she can plan a
mid-afternoon country bike ride with her kids. “If you look at my initials,” Melanie Often Manis adds, “I'm really Dr. MOM.”