Ken Bischoff has been called the “Father of Physiological Pharmacokinetics.” This paper will discuss the way in which this came about during his remarkable work with the National Institutes of Health. I had joined NIH in 1966 to develop a chemical engineering section. Ken had developed some theory for drug distribution in mammals in collaboration with Bob Brown from the Department of Pharmacology of the University of Texas at Austin. Ken was interested in moving to a location where he could have more interaction with the medical community. Thus our interests coincided perfectly. He moved to the University of Maryland in 1967 and worked with us as time permitted for several years. I will explore this period through discussion of three key publications.

Ken greatly extended his work on the application of chemical reaction engineering (in which he was a world authority) to problems of drug distribution in the body. The field is known as pharmacokinetics, but we didn't know the term when we started. Our first refereed publication was “Thiopental Pharmacokinetics,” J Pharm Sci 57:1346-1351, 1968. This was influenced by Jim Gillette, of the Laboratory of Chemical Pharmacology of the National Heart Institute, who had stressed the importance of tissue uptake in the distribution of drugs. I had been interested in the physiologic limitations that might occur if we developed devices capable of very rapid removal of substances from the blood by hemodialysis or hemoperfusion. One of the known problems was disequilibrium in the brain, which was thought to be osmotic. This led us to the laboratory of Dave Rall, who suggested the general problem of accounting for species differences in pharmacokinetics. Dave was Assistant Scientific Director of the National Cancer Institute. In addition to his expertise on the blood-brain barrier, he was concerned with the very basic issue of determining how to extrapolate pharmacologic data obtained in mice to humans for the effective introduction of drugs into the clinic. He got us together with Dan Zaharko, a physiologist from the University of Indiana who came to NIH in July of 1968 as a Special Fellow in pharmacology research. Our group also included Jim Longstreth, who was working in the Chemical Engineering Section on a two-year appointment during his doctoral studies at Johns Hopkins. The personalities and talents of the group came together well to produce an amazing collaboration. The collaboration resulted in the publication of (among others) “Interspecies correlation of plasma concentration history of methotrexate,” Cancer Chemotherapy Rep 54:95-101, 1970, and “Methotrexate pharmacokinetics,” J Pharm Sci 60,1128-1133, 1971. The second paper is generally acknowledged to be the seminal publication in the field of physiological pharmacokinetics, often now called physiologically-based pharmacokinetics (PBPK). In addition to various applications in pharmacology, the methodology has been used extensively in describing and predicting the behavior of environmental toxins in experimental animals and in humans. The methodology is natural for this because of its predictive power. Pharmacologists have the luxury of evaluating drugs in human subjects; toxicologists are generally not able to do this.

The “Methotrexate pharmacokinetics” paper earned for Ken the 1971 Ebert Prize of the Academy of Pharmaceutical Sciences. The Ebert Prize established, in 1873, is the oldest award in its field and is given for the best original report published in the Journal of Pharmaceutical Sciences in the previous year. The paper was further recognized as a Citation Classic by the Institute for Scientific Information in 1989. It is still used and has now accumulated more than 400 citations.

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