1978–1998: The Benet Chairship
In July 1978, Leslie Z. Benet, PhD, became the third chair of the department. Benet enunciated seven goals that he hoped would be accomplished during his tenure:
- Maintain and increase the excellence of pharmacokinetic/pharmacodynamic expertise within the department.
- Develop outstanding pharmaceutical science expertise in innovative areas of drug delivery and research.
- Markedly increase NIH-funded research within the department.
- Innovate departmental entrepreneurial activities to enhance the recognition and reputation of the department and to serve as a source of unencumbered funds to facilitate department operations.
- Establish the pharmaceutical sciences as a discipline, expanding its influence beyond the boundaries of the pharmacy profession.
- Increase the numbers of female pharmaceutical science faculty within the department.
- Facilitate the further development of the Division of Clinical Pharmacy to attain departmental status.
The department chose to expand its basic science expertise through recruitments in liposomal and transdermal drug delivery. Initial recruitments in these areas, respectively, were Francis C. Szoka, Jr., PhD, and Richard H. Guy, PhD. Both of these appointments led to the development of world-class programs within the department.
Additional faculty recruitments in these areas included Joseph E. Bentz, PhD, Ronald C. Wester, PhD, and Christopher Cullander, PhD. Further recruitments included Frances M. Brodsky, DPhil, for expertise in immunology (specifically, clathrin mediated peptides), and Ronald A. Siegel, ScD, for expertise in polymeric drug delivery systems. The department also began its influence on computational biology/informatics with the recruitment of Patricia C. Babbitt, PhD. Babbitt and Anthony Hunt were instrumental in the department’s obtaining a National Institutes of Health Biotechnology Research and Training grant, a University of California Biotechnology Research and Education grant for Training in the Rational Design and Delivery of New Drugs (proteins), and the establishment of the Oligonucleotide Biotechnology Program at UCSF. Members of the department (initially Guy, Hunt, Siegel, and Szoka) were active participants in the UCSF/UC Berkeley Joint Graduate Group in Bioengineering, training graduate students and carrying out bioengineering research projects. This interaction of department faculty members continued until the eventual merger, as described in the 2009–2014 history that follows.
Division of Toxicology
During the mid-1980s the University, School of Medicine, and School of Pharmacy approved the establishment of a Division of Toxicology within the Department of Pharmacy to include a toxicology training program of 16 graduate students and two new state-funded faculty positions with the allocation of a full floor of research space at the newly obtained Laurel Heights campus. Neal Castagnoli, Jr., PhD, was named the first division director. The division rapidly achieved funding from the University of California Toxic Substances Research and Teaching Program and from a National Institute of Environmental Health Sciences (NIEHS) SuperFund Program Project grant. Castagnoli, Suzanne P. Hawkes, PhD, Thomas Meehan, PhD, and Thomas P. Singer, PhD, comprised the initial faculty.
When Castagnoli left UCSF in 1987 to assume an endowed chairship at Virginia Tech University, an international search for a new chief of the division was undertaken. The search committee identified a number of candidates with outstanding (e.g., National Academy) credentials, and the candidates confirmed their interest. However, the campus was unable to obtain the approval of the city of San Francisco for operating laboratories at Laurel Heights, thereby eliminating the new campus space for toxicology use. The financial crisis in California in the late 1980s compounded the difficulty in establishing the division. The state provided only 50 percent funding for one of the two new faculty positions and funding for the newly allocated 16 graduate student positions was withheld. This curtailed the proposed toxicology division activities, although the graduate student and faculty positions continued to be attributed to the department.
Clinical Pharmacology had a more favorable trajectory. When the division chief, Kenneth Melmon, MD, left UCSF in 1978 to chair Stanford’s Department of Medicine, the UCSF Department of Pharmacy negotiated with the UCSF Department of Medicine to make Clinical Pharmacology a joint division between the two departments. Most importantly, the newly re-constituted Division of Clinical Pharmacology would no longer be responsible for generating patient care dollars for the School of Medicine through a consultation service. Rather faculty members in the Division became responsible only for generating NIH-funded research and salary support in the same manner as basic science faculty members in the Department of Pharmacy. This latter agreement eliminated any conflict between faculty members in the School of Medicine and those in the Clinical Pharmacy consultation services of the School of Pharmacy in relation to drug dosing recommendations in patients.
After an interim period, Neal L. Benowitz, MD, became chief of the Division of Clinical Pharmacology. Roger L. Williams, MD; Nicholas Holford, MD; and Janice B. Schwartz, MD, held joint full-time faculty appointments in the division. Funding for two additional faculty members, Lewis B. Sheiner, MD, and Stewart L. Beal, PhD, was negotiated with the Department of Laboratory Medicine in exchange for closing the Clinical Pharmacokinetics Laboratory of the Department of Pharmacy and transferring its drug assay responsibilities to the Department of Laboratory Medicine. Dividing the assay of narrow therapeutic index drugs between Pharmacy and the Department of Laboratory Medicine had turned out to be financially unproductive, making it reasonable to trade the closing of the pharmacy laboratory for faculty funding.
A major goal of the department was to markedly increase NIH-funded research. In 1977–1978, NIH research grant funding to the department totaled only $215,000; but in 1979 the department was awarded a Center Grant from the NIH Institute of General Medical Sciences under the title, “Drug Pharmacokinetics–Drug Pharmacodynamics.” This grant, along with the Department of Pharmaceutical Chemistry’s excellent funding record, put the UCSF School of Pharmacy in the #1 ranking for federal research funding awarded to Schools of Pharmacy. The School has maintained this top standing to this day. The center grant, with Benet as principal investigator, continued to receive funding for 20 years, and at various times provided research funding for department researchers Beal, Benet, Benowitz, Brodsky, Giacomini, Hoener, Øie, Schwartz, Sheiner, Siegel, and Szoka, and to faculty members from other departments in the schools of medicine and dentistry. Within 10 years of setting the goal to significantly increase NIH support, funding levels in the department reached $3.4 million in 1988—an increase of more than 15-fold.
Recognition for the department was strongly enhanced by the increased pharmacokinetic and pharmacodynamic capabilities of the joint Division of Clinical Pharmacology. In the August 1982 issue of the Journal of Pharmacokinetics and Biopharmaceutics, editors Benet and Rowland announced the initiation of a new section of the journal under the title “Pharmacometrics,” with Sheiner as the section editor. Through the late 70s and early 80s, Beal and Sheiner developed the NONMEM software package for population pharmacokinetic modeling. As noted in Wikipedia, “Its name is an acronym for non-linear mixed effects modeling and has become the ‘gold standard,’ both in the pharmaceutical industry and academia.”
Leading department publishing
Faculty recruitments of Kathy M. Giacomini, PhD; Deanna L. Kroetz, PhD; Robert A. Upton, PhD; and Davide Verotta, PhD, further enhanced the department’s reputation for excellence in pharmacology, pharmacokinetics, and pharmacodynamics. These new faculty members solidified the department’s leadership by making significant contributions to the literature. Benet and Sheiner prepared an appendix of pharmacokinetic data, entitled Design and Optimization of Dosing Regimens, for the sixth (1980) edition of Goodman and Gilman’s The Pharmacological Basis of Therapeutics. In the 1985, 1990, and 1996 editions of this “bible of pharmacology,” department members wrote the Pharmacokinetics chapter (under General Principles) and the appendix. Authors included Benet, Sheiner, Kroetz, Øie, Schwarz, and Williams. In 1981, Rowland and Tozer collaborated to compile their classroom lectures and scientific insights into the first edition of the textbook Clinical Pharmacokinetics. This book quickly became the leading text in the field, adopted as the primary student resource in many schools of pharmacy and divisions of clinical pharmacology worldwide. The fourth edition of the textbook was published in 2011 under the expanded title Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications.
Drug Studies Unit
Another department goal was to innovate entrepreneurial activities to enhance the recognition and reputation of the department, and to serve as a source of unencumbered funds to facilitate department operations. In 1977, under the leadership of Riegelman and Benet, the department established the first academic-based contract research organization (CRO) to carry out quality pharmacokinetic and pharmacodynamic human clinical studies. The Drug Studies Unit (DSU) had a clinical component, directed by Roger Williams, MD, and analytical and data analysis units, initially both directed by Robert Upton, PhD, but subsequently the analytical unit was directed by Emil T. Lin, PhD, and the data analysis unit by Nancy Sambol, PharmD. During its first 10 years, the DSU exhibited remarkable financial success, with revenues rising to $3.2 million per year. In addition, the DSU brought two drug products to market. The first, Maxide™ was a new combination of hydrochlorothiazide and triamterene that yielded significantly better bioavailability and a different drug dose ratio with comparable efficacy as compared to the world-leading product Dyazide™. Maxide was sold to Mylan Pharmaceuticals, who licensed the product to Lederle Laboratories. For many years, Maxide was among the top 200 drugs prescribed in the United States. The department published a number of papers related to the development of the drug, with Williams, Upton, and Benet as senior authors.
In addition, the DSU was largely responsible for carrying out the Phase I and Phase II studies for metformin that led to the approval of this blockbuster anti-diabetic drug. Metformin was developed by Lipha, a small French company that lacked clinical research facilities. Lipha contracted with the DSU to carry out Phase I and II studies. The drug was sold to Bristol-Myers Squibb and it is today marketed as Glucophage™. Papers describing this work were published with senior authors Sambol, Lin, and Benet.
The success of the DSU attracted many competitors, mostly in the non-academic arena. By the early 1990s, increasing university and state regulations—but primarily being underbid for contracts by the commercial sector—led to the closure of the clinical unit. However, the analytical unit under the leadership of Lin, followed by Yong Huang, PhD, continued to be financially competitive and successful for many years. The data analysis unit of DSU also continues to function at a moderate level under Sambol’s direction.
Pharmacokinetics for Pharmaceutical Scientists
In 1987, the department’s annual Pharmacokinetics for Pharmaceutical Scientists Course (PK Course) was established, under the leadership of Tozer, Øie, Giacomini, and Benet. This one-week intensive pharmacokinetic training course underwent significant changes as the field developed. More than 2,000 pharmaceutical scientists from various organizations worldwide have matriculated. The 27th Annual PK Course was held in February 2014, under the leadership of Benet and Upton, with several of our present and emeritus faculty—including those in diverse locations around the world—returning to San Francisco to deliver lectures and to lead workshops. Many former graduate students and clinical pharmacology fellows trained at UCSF have also returned to serve over the years as workshop leaders.
Faculty members in the department were entrepreneurs, forming new drug companies. Patents filed through the University and licensed to these companies—along with stock donations—provided further entrepreneurial funding to the department, in addition to funds generated by the DSU, the PK Course, and the NONMEM license.
The UCSF School of Pharmacy, with strong support from Deans Daniels and Goyan, was a leader in the hiring of non-pharmacist basic science faculty to teach in schools of pharmacy. This posed a problem for faculty members in the Department of Pharmacy for two reasons. First, it was more difficult for non-pharmacist basic science faculty members to teach the Department of Pharmacy courses in the curriculum, since these courses are more closely related to the everyday practice of the profession, i.e., dosage form characteristics, drug bioequivalence, drug disposition, which underlay the basic principles upon which the clinical pharmacist makes dosage regimen decisions.
Secondly, no scientific society outside of the pharmacy practice profession truly represented the scientific discipline of the basic scientists in the Department of Pharmacy. This was not true for the Department of Pharmaceutical Chemistry, where American Chemical Society meetings were the primary research interface attended by faculty members and graduate students. In contrast, Department of Pharmacy basic science faculty members and graduate students were members of the Academy of Pharmaceutical Sciences, an association that was a subdivision of the professional society, the American Pharmaceutical Association (APhA). During its 20-year history, the Academy numbered only about 2,300 scientists. Non-pharmacist scientists were not attracted to this subdivision of the Pharmacy profession, and if they did join they did not have voting privileges in the APhA.
UCSF Department of Pharmacy leadership was instrumental in the formation of the American Association of Pharmaceutical Scientists (AAPS), an organization created to recognize the pharmaceutical sciences as a discipline influential beyond the pharmacy profession. AAPS was established in 1986, with Benet as a founder and first president and Kenneth L. Lem, PharmD, as the first executive director. The official journal of the new association, Pharmaceutical Research, was founded and edited by Wolfgang Sadee, PhD. A third scientific journal was founded within the department under the editorship of Sadee in 1999, when The AAPS Journal became one of the first online-only publications. AAPS had more than 10,000 members in 2014, with approximately 20 percent international members, making it both the largest national and international association of pharmaceutical scientists.
Name change: Department of Biopharmaceutical Sciences
As noted in the listing of departmental faculty, the goal of increasing female faculty members was reached. There was also progress toward the goal of achieving departmental status for the Division of Clinical Pharmacy.
In the early 1990s, as mentioned earlier, faculty felt that the name Department of Pharmacy did not accurately represent the scientific breadth of departmental work. Consensus on a new name was reached in 1996, when Department of Biopharmaceutical Sciences was adopted as the department name.
Major departmental scientific contributions (1978–1998)
- Discovered potential for significant first pass intestinal metabolism via Cytochrome P-450 3A enzymes, initially identified for calcineurin inhibitor immunosuppressives, and methodology to characterize intestinal versus hepatic first pass effect
- Discovered the importance of transporter-enzyme interplay in the intestine and liver; issued patent for inhibiting intestinal enzymes and efflux transporters to increase drug bioavailability
- Published seminal paper predicting skin permeability
- Received patent for use of reverse iontophoresis for noninvasive glucose monitoring, leading to FDA-approved product GlucoWatch®
- Discovered metabolic bioactivation of the parkinsonian-inducing agent MPTP by mitochondrial monoamine oxidase B
- Cloned and characterized first human organic cation transporter, OCT1, the major uptake transporter for metformin and many other important drugs
- Cloned and characterized first human purine nucleoside transporter, CNT2
- Increased understanding of dose-effect relationship
- Introduced population pharmacokinetics and methods for parameter estimation
- Forecasted individual pharmacokinetics using a Bayesian approach
- Defined importance of modeling interoccasion variability in population pharmacokinetic analyses
- Enunciated and defined “Learning versus Confirming” approach to clinical drug development
- Published seminal paper on integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug development
- Evaluated pharmacokinetic and pharmacodynamic models using the posterior predictive check
- Developed NONMEM and taught principles of mixed effects modeling
- Published seminal paper on polymorphic enzymes and adverse drug reactions
- Identified noncompartmental relationship between clearance, volume of distribution steady-state (Vss) and mean residence time (MRT) and methodology for noncompartmental determination of Vss; application of MRT concepts to characterize absorption and dissolution
- Recognized potential of and mechanism for carboxylic drugs to mediate covalent binding via acyl glucuronide and acyl CoA metabolites
- Directed research leading to patents and to FDA-approved anticancer-liposome formulation of doxorubicin, Doxil®, and the lipid complex antifungal formulation of amphotericin B, Amphotec®
- Devised mechanisms for DNA delivery by polycationic liposomes and polymers
- Devised, synthesized, and patented branched cationic dendrimers that led to the commercialized transfection reagent Superfect®
- Designed and characterized first pH responsive peptide (GALA) and suggested mechanisms of pore formation and membrane destabilization
- Established key features of clathrin biochemistry and the role of clathrin pathways in the immune response
- Developed the Drug Targeting Index, which builds on clearance concepts to provide a guide for selecting drug candidates that are suitable for regional delivery or targeting by nanocarriers
- Produced seminal studies on swelling equilibria, kinetics, and drug release properties of pH-sensitive hydrophobic hydrogels
- Detected spontaneous opioid receptor signaling and its relevance to opioid dependence
- Discovered neutral opioid antagonists as potential drugs in treatment of opioid addiction and adverse effects
Image credits: C. Krieg for Leslie Benet; Frank Farm for Laurel Heights campus; Kaz Tsuruta for Christopher Cullander and Frances Brodsky; David Powers for Kathy Giacomini; © Majed for Deanna Kroetz; Elisabeth Fall for Davide Verotta and Emil Lin
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