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Grant Wilkinson, Ph.D., will be on hand for the debut next week of a Distinguished Lectureship in Clinical Pharmacology bearing his name. photo by Anne Rayner

Wilkinson lauded for collegiality, vision; lectureship set

BY: BILL SNYDER

1/14/2005 - The body is a marvelously complicated and confounding place, especially when you're trying to deliver a drug to its target without causing havoc somewhere else.

Thanks to scientists like Vanderbilt's Grant R. Wilkinson, Ph.D., D.Sc., many of the stumbling blocks to effective drug delivery have been — and are being — discovered.

Wilkinson, a professor of Pharmacology whose published research papers are among the most frequently cited by pharmacologists worldwide, will be honored next week with the establishment of a distinguished lectureship in his name.

“Grant Wilkinson is one of the true giants in the field of drug disposition and metabolism,” said Jason D. Morrow, M.D., director of the Division of Clinical Pharmacology. “His seminal studies have paved the way for many of the modern concepts of drug metabolism.”

“Grant Wilkinson's laboratory has for over three decades been at the forefront of efforts to identify mechanisms underlying variability in drug actions among patients,” added Dan M. Roden, M.D., director of the recently established John A. Oates Institute for Experimental Therapeutics. “This is the essence of modern Clinical Pharmacology, and his work has had a huge impact on patient care and on the way drugs are developed.”

The British native is also well regarded here for his collegiality, vision and mentoring skills. “Grant has been an incredible friend and mentor,” said Richard B. Kim, M.D., professor of Medicine and Pharmacology, who began working with Wilkinson in the early 1990s as a post-doctoral fellow. “He's really been a visionary in terms of … where the field is moving.”

Wilkinson, who joined the Vanderbilt faculty in 1971, credited John A. Oates, M.D., former director of the Division of Clinical Pharmacology, with fostering a nurturing environment for young scientists emphasizing both basic and translational research. “What I appreciated was the freedom,” he said.

For the bulk of his career, Wilkinson has tried to understand why individual patients vary so much in their response to drugs. In the mid-1970s, he and his colleagues developed a quantitative model to explain how enzymes in the liver metabolize, or break down, a portion of orally ingested drugs before they can reach the bloodstream — known as the “first-pass phenomenon.”

The model is based on the concept of “intrinsic clearance,” the efficiency with which a cell, such as a liver cell, can metabolize a drug. It enables researchers and pharmaceutical companies to predict how disease, other medications, alcohol and even dietary substances can affect a drug's pharmacokinetics — the way it is absorbed, distributed and metabolized.

Another factor is genetics. Wilkinson and his colleagues, including F. Peter Guengerich, Ph.D., director of the Center in Molecular Toxicology, identified polymorphisms — or genetic differences — in a group of liver enzymes called cytochrome P450 that metabolize drugs.

In the early 1980s, Wilkinson's group reported finding a genetic defect in one of these enzymes, called CYP2C19, which is associated with poor metabolism of the anti-convulsant drug mephenytoin, especially among people of Japanese ancestry. This was the first discovery of a genetic defect in this enzyme that affects the metabolism of a number of important drugs. It helped lead to an appreciation of racial and ethnic differences in drug metabolism.

Drug companies now can predict which enzymes, including CYP2C19 and other polymorphically distributed enzymes, are important in the metabolism of their candidate drugs by testing the agents first in the laboratory in enzyme-containing vesicles called microsomes that have been isolated from human liver.

For the past several years, Wilkinson has studied a subfamily of cytochrome P450 enzymes, called CYP3A, that are present in both the liver and the intestine, and which may be the most important group of drug-metabolizing enzymes in humans. Many of the same drugs broken down by these enzymes also are pumped out of cells by a transporter called P-glycoprotein, preventing their absorption in the first place.

In 1998, Wilkinson, Kim and their colleagues, including Roden and Alastair J.J. Wood, M.D., professor of Medicine and Pharmacology, reported that the P-glycoprotein pump limits absorption and entry into the brain of a class of AIDS drugs called protease inhibitors. This discovery helped spur efforts to block the transporter in order to increase absorption and transport across the blood-brain barrier.

Wilkinson continues to contribute to understanding of the role that genetics plays in drug disposition and metabolism. He said he was skeptical, however, that this knowledge one day will enable doctors to “personalize” therapy — prescribe drugs to patients who are most likely to respond and least likely to experience side effects.

Genes are just one determinant in drug metabolism, he cautioned. “We know from clinical experience that a patient's age, the diet and other factors all play a role and, in many instances, more than one gene is involved which enormously complicates the situation.”

LECTURESHIP SET FOR JAN. 18

Grant R. Wilkinson, Ph.D., D.Sc., one of Vanderbilt's most well-published pharmacology researchers, will be honored Tuesday, Jan. 18, with the establishment of a Distinguished Lectureship in Clinical Pharmacology in his name, and an afternoon of activities.

The events begin at 1:30 p.m. with a tour of the Division of Clinical Pharmacology, the General Clinical Research Center and other areas of the Medical Center. The tour will depart from the North Lobby of Light Hall.

The endowed lectureship will be formally announced at 3 p.m. in room 208 Light Hall, followed by the first lecture by William E. Evans, Pharm.D., Director and CEO of St. Jude Children's Research Hospital in Memphis.

Evans' talk is entitled “From Pharmacogenetics to Pharmacogenomics: Gene Expression Profiling to Identify Determinants of Drug Response.” Following the talk, a reception will be held at 4:30 p.m. in the North Lobby of Light Hall.

For more information, contact Barbara Weaver in the Division of Clinical Pharmacology at 2-3033.

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