Perspectives on a pharmacokinetics legend: C versus T (contributions over time)

Abstract

Leslie Z. Benet is Professor and Former Chair at the University of California San Francisco (UCSF), Department of Bioengineering and Therapeutic Sciences, and Department of Pharmaceutical Chemistry. Professor Benet has had a profound impact on the development of fundamental concepts in pharmacokinetics, and the application of these principles in patient care and drug development. This theme issue is dedicated to Professor Benet in tribute to his significant contributions to the pharmaceutical sciences. An outstanding commentary that details Professor Benet's career path and scientific achievements over the past 50 years was published recently in Pharm Res.1.Smith D.E. Rowland M. Giacomini K.M. Amidon G.L. Dedication to professor Leslie Z. Benet: 50 years of scientific excellence and still going strong!.Pharm Res. 2012; 29: 2345-2353Crossref PubMed Scopus (3) Google Scholar We chose to provide a different perspective for the reader by focusing this commentary on those intangible factors that make Professor Benet truly a legend in the pharmaceutical sciences. In gathering information for this “C versus T” commentary, we interviewed Professor Benet and contacted scientific colleagues, professional mentees, and family. We asked each to share a brief perspective from their vantage point on this giant in the field. Many great “Les Benet” attributes emerged including energy, passion for science, visionary, willingness to embrace new ideas and try new things, boldness to speak out, even if he might subsequently be proved wrong, breadth of perspective, positive attitude, global engagement, respect and encouragement of others regardless of nationality, gender or scientific stature, and enthusiasm to address challenging issues. These characteristics clearly are evident in the comments that follow. Les' propensity to boldly take the “less traveled path” started at an early age. Even though he came from a family of pharmacists, he aspired to be a poet and majored first in English. However, his academic focus shifted from the humanities, English literature, and creative writing to pharmaceutical chemistry when he entered graduate school. What might be viewed by some as an incomprehensible change in direction undoubtedly provided Les with a breadth of perspectives and emphasized his willingness to embrace new ideas and try new things, which remains a hallmark of Les' personality. Pharmacokinetics is so logical compared with the English language…no wonder Les excelled! Building from a foundation in physical pharmacy, his positive and significant impact in the application of pharmacokinetic concepts has been noteworthy. Here, J Pharm Sci has played a special role. Dr. Benet published his first scientific paper in J Pharm Sci in 1965.2.Benet L.Z. Goyan J.E. Determination of the stability constants of tetracycline complexes.J Pharm Sci. 1965; 54: 983-987Abstract Full Text PDF PubMed Scopus (35) Google Scholar His most highly cited paper “Noncompartmental Determination of the Steady-State Volume of Distribution” also was published in J Pharm Sci in 19793.Benet L.Z. Galeazzi R.L. Noncompartmental determination of the steady-state volume of distribution.J Pharm Sci. 1979; 68: 1071-1074Abstract Full Text PDF PubMed Scopus (709) Google Scholar (cited more than 900 times). This article also remains the most highly cited article in J Pharm Sci, out of more than 18,000 articles. Professor Benet's assessment of the pharmacokinetic literature in the late 1960s and early 1970s was that “the discipline, as practiced, was much too complicated mathematically (unnecessarily) to have a major impact on drug therapy.”4.Benet L.Z. Benet L Z and Galeazzi R L: Noncompartmental determination of the steady-state volume of distribution, J Pharm Sci 68, 1071–1074, 1979—The backstory.AAPS J. 2012; 14: 164-167Crossref PubMed Scopus (3) Google Scholar He set out to simplify basic pharmacokinetic parameters with the intent of improving the relevance and application of fundamental concepts.5.Benet L.Z. Ronfeld R.A. Volume terms in pharmacokinetics.J Pharm Sci. 1969; 58: 639-641Abstract Full Text PDF PubMed Scopus (42) Google Scholar, 6.Benet L.Z. Turi J.S. Use of general partial fraction theorem for obtaining inverse laplace transforms in pharmacokinetic analysis.J Pharm Sci. 1971; 60: 1593-1594Abstract Full Text PDF PubMed Scopus (26) Google Scholar, 7.Benet L.Z. General treatment of linear mammillary models with elimination from any compartment as used in pharmacokinetics.J Pharm Sci. 1972; 61: 536-541Abstract Full Text PDF PubMed Scopus (171) Google Scholar One of his most important articles addressed clearance concepts.8.Rowland M. Benet L.Z. Graham G.G. Clearance concepts in pharmacokinetics.J Pharmacokinet Biopharm. 1973; 1: 123-136Crossref PubMed Scopus (629) Google Scholar This classic paper, which was published in 1973, is his 2nd most cited article (cited more than 600 times). Of course, the inter-relationship between volume of distribution, clearance, and half-life are common knowledge today, but at the time, the significance of these parameters on drug disposition was not appreciated widely in the fields of pharmacy or medicine. The collaborative environment at the University of California San Francisco, including Professors Sidney Riegelman, Malcolm Rowland, and Lewis Sheiner provided a think-tank for the very fruitful development of the discipline. Apart from the early publications delineating pharmacokinetic principles, Professor Benet has focused on connecting applied science and clinical science with these principles throughout his 50 years of scientific productivity in an effort to improve drug therapy outcomes in patients. A major contribution has been the understanding of the role of enzymes in the gastrointestinal tract, and the interplay between transporters and enzymes.9.Benet L.Z. Cummins C.L. Wu C.Y. Transporter-enzyme interactions: Implications for predicting drug-drug interactions from in vitro data.Curr Drug Metab. 2003; 4: 393-398Crossref PubMed Scopus (167) Google Scholar, 10.Wu C.Y. Benet L.Z. Hebert M.F. Gupta S.K. Rowland M. Gomez D.Y. Wacher V.J. Differentiation of absorption and first-pass gut and hepatic metabolism in humans: Studies with cyclosporine.Clin Pharmacol Ther. 1995; 58: 492-497Crossref PubMed Scopus (338) Google Scholar, 11.Wacher V.J. Wu C.Y. Benet L.Z. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: Implications for drug delivery and activity in cancer chemotherapy.Mol Carcinog. 1995; 13: 129-134Crossref PubMed Scopus (825) Google Scholar The very elegant work using erythromycin as a probe substrate to examine the effects of uremic toxins on hepatic drug elimination,12.Sun H. Frassetto L.A. Huang Y. Benet L.Z. Hepatic clearance, but not gut availability, of erythromycin is altered in patients with end-stage renal disease.Clin Pharmacol Ther. 2010; 87: 465-472Crossref PubMed Scopus (52) Google Scholar, 13.Sun H. Huang Y. Frassetto L. Benet L.Z. Effects of uremic toxins on hepatic uptake and metabolism of erythromycin.Drug Metab Dispos. 2004; 32: 1239-1246Crossref PubMed Scopus (108) Google Scholar evaluate transporter–enzyme interplay,14.Frassetto L.A. Browne M. Cheng A. Wolfe A.R. Roland M.E. Stock P.G. Carlson L. Benet L.Z. Effects of uptake and efflux transporter inhibition on erythromycin breath test results.Clin Pharmacol Ther. 2007; 81: 828-832Crossref PubMed Scopus (45) Google Scholar, 15.Lam J.L. Okochi H. Huang Y. Benet L.Z. In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: Characterizing the importance of transporter-enzyme interplay.Drug Metab Dispos. 2006; 34: 1336-1344Crossref PubMed Scopus (74) Google Scholar and determine sex and menopause-related differences in this interplay16.Cummins C.L. Wu C.Y. Benet L.Z. Sex-related differences in the clearance of cytochrome P450 3A4 substrates may be caused by P-glycoprotein.Clin Pharmacol Ther. 2002; 72: 474-489Crossref PubMed Scopus (150) Google Scholar, 17.Harris R.Z. Tsunoda S.M. Mroczkowski P. Wong H. Benet L.Z. The effects of menopause and hormone replacement therapies on prednisolone and erythromycin pharmacokinetics.Clin Pharmacol Ther. 1996; 59: 429-435Crossref PubMed Scopus (42) Google Scholar are excellent examples of his ingenious way of thinking about drug kinetics Another important contribution has been the incorporation of “drug disposition” into the biopharmaceutics classification system (BCS), not only figuratively (hence the new acronym for biopharmaceutics drug disposition classification system, “BDDCS”), but also literally, by expanding the classification system to include metabolic and transport processes. This new classification system provides a framework for predicting the in vivo disposition characteristics of new molecular entities at an early stage in drug discovery and development.18.Wu C.Y. Benet L.Z. Predicting drug disposition via application of BCS: Transport/absorption/ elimination interplay and development of a biopharmaceutics drug disposition classification system.Pharm Res. 2005; 22: 11-23Crossref PubMed Scopus (1087) Google Scholar, 19.Benet L.Z. Amidon G.L. Barends D.M. Lennernas H. Polli J.E. Shah V.P. Stavchansky S.A. Yu L.X. The use of BDDCS in classifying the permeability of marketed drugs.Pharm Res. 2008; 25: 483-488Crossref PubMed Scopus (108) Google Scholar, 20.Benet L.Z. Broccatelli F. Oprea T.I. BDDCS applied to over 900 drugs.AAPS J. 2011; 13: 519-547Crossref PubMed Scopus (477) Google Scholar, 21.Benet LZ. The role of BCS (biopharmaceutics classification system) and BDDCS (biopharmaceutics drug disposition classification system) in drug development.J Pharm Sci. 2013; 102: 34-42Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, 22.Broccatelli F. Cruciani G. Benet L.Z. Oprea T.I. BDDCS class prediction for new molecular entities.Mol Pharm. 2012; 9: 570-580Crossref PubMed Scopus (70) Google Scholar Combining BDDCS and the uremic toxin transporter inhibition was the subject of his 2013 Ebert Prize paper.23.Reyes M. Benet L.Z. Effects of uremic toxins on transport and metabolism of different biopharmaceutics drug disposition classification system xenobiotics.J Pharm Sci. 2011; 100: 3831-3842Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar In more recent years, his published papers on the “operational multiple dosing half-life” to explain drug accumulation in patients, and the influence of dosage form and dosing interval, are yet another example of his efforts to rationally apply pharmacokinetic principles to optimize pharmacotherapy.24.Sahin S. Benet L.Z. The operational multiple dosing half-life: A key to defining drug accumulation in patients and to designing extended release dosage forms.Pharm Res. 2008; 25: 2869-2877Crossref PubMed Scopus (66) Google Scholar His many significant scientific contributions are described more comprehensively by Smith et al.1.Smith D.E. Rowland M. Giacomini K.M. Amidon G.L. Dedication to professor Leslie Z. Benet: 50 years of scientific excellence and still going strong!.Pharm Res. 2012; 29: 2345-2353Crossref PubMed Scopus (3) Google Scholar in their commentary. Professor Benet's awards and accomplishments are too numerous to detail in the space allotted. Of note, he has been awarded eight honorary doctorates from Europe and the United States, the first one in 1987 from Uppsala University, Sweden. He has been the recipient of many prestigious awards, most notably the Higuchi Research Prize in 2000, and the Ebert Prize in 2013. Professor Benet has been cited more than 19,000 times, with more than 17,500 citations by other authors. During the last 4 years, his publications have been cited 900–1100 times per year. In addition to his impressive publication record, he has supervised more than 50 Ph.D. students, and more than 100 postdoctoral research personnel and visiting scholars. These individuals represent the next generation of leaders in the pharmaceutical sciences, and his true legacy. Leslie Z. Benet was instrumental in creating the American Association of Pharmaceutical Scientists (AAPS) in 1986. These were turbulent times as pharmaceutical scientists struggled to gain recognition in pharmacy's powerful society, the American Pharmaceutical Association (APhA). Professor Benet's vision that the Academy of Pharmaceutical Sciences (APS) was one of the crown jewels of APhA, and that this discipline needed recognition, both within and external to the profession of pharmacy, culminated in the formation of AAPS. Although AAPS originally was conceived by Les as a group within APhA, because of organizational issues, this was not fulfilled and AAPS was created as an independent organization. Since the birth of AAPS, the pharmaceutical science disciplines have developed tremendously and are recognized increasingly as strong contributors to the entire health system. Professor Benet, who is a pharmacist by training, remains a strong supporter of APhA (as a >50 year member) and all aspects of the pharmacy profession. One of the areas where Professor Benet has been particularly influential is in globalization of the pharmaceutical sciences. He frequently invited wonderfully interactive international postdoctoral scholars, including European and Japanese pharmaceutical scientists, to UCSF. He was instrumental in initiating the Japanese American Pharmacokinetics and Biopharmaceutics Conferences, and in engaging Japanese scientists to become involved in the International Pharmaceutical Federation (FIP), which was primarily a European society. The expansion of FIP to become a truly international organization, with connections to AAPS and to the Japanese societies, was inspired by Professor Benet. Also the Pharmaceutical Sciences World Congress was initiated by Professor Benet in San Francisco in 2000, and has been held every 3–4 years at various venues around the world. For more than 50 years, Professor Benet has continued to have a profound impact on the careers of young scientists (and even “not so young” scientists) as evidenced by numerous honors and awards, including the prestigious outstanding faculty mentor award at UCSF. His advocacy for the scientific education, research training, and career development of PharmDs and women in a predominantly male- and Ph.D.-dominated era, is noteworthy. His advice to younger scholars is to be on the cutting edge, but to remember your roots and your strengths. As pharmaceutical scientists, we can be truly translational in our approaches by integrating cellular and clinical knowledge. It is imperative to use new technologies and methods in our approaches to answer translational questions. We have the training and expertise to do that much better than most scientists from other disciplines. However, sometimes the breadth of our knowledge may be perceived by outsiders as a negative aspect that detracts from a more focused approach. Of course, it is our breadth of knowledge that enables us to translate from the bench to the bedside and from the patient to the population. Professor Benet's grand vision for the pharmaceutical sciences is a discipline that combines the basic and clinical sciences to optimize drug therapy. He believes that improving biomarkers, surrogate markers and clinical endpoints will be a critical area of focus in the coming years. He is, of course, already working in this area, as well as in the area of microfluidics and “hepatocytes on a chip” to predict metabolism and minimize the use of experimental animals. As for pharmacokinetics, Professor Benet reminds us that it is just a tool…a really good and useful tool! It is a way of quantitative thinking that gives us unique insights when combined with a clinical perspective. Professor Benet may be most well-known for the introduction of new ideas and concepts in the pharmaceutical sciences, which often are controversial and thought provoking, and stimulate much healthy discussion. He stands up for what he believes, and is not afraid to be wrong (although his hypotheses usually prove to be correct!). Les finds data or results that are not consistent with conventional theory even more interesting, because there is something new to be learned. Those are words from a true scientist! We represent many individuals worldwide who are grateful for his forward thinking and his mentorship over the years. The following comments provide unique perspectives of this giant in the field. For over a half a century of my adult life, I have been blessed to have shared it with Leslie. When he enters the room it is like a light turns on. His humor, kindness, love of the new and exciting, optimism, and energy is infectious. Every day is a new adventure for him and he greets it with enthusiasm. Leslie is an inspiration for his students and for all of us. He loves life, his family—me, his children and grandchildren, his work, and the San Francisco Giants. To Dr. Leslie Benet, my graduate study mentor and a life-long educator. After more than 27 years, I still say that it's the most rewarding and inspiring experience to have studied in Dr. Leslie Benet's laboratory at UCSF. The solid training and exposure to research and Les's life coaching has been instrumental in shaping me as a scientist and a person. Many have already elaborated on Dr. Benet's scientific excellence, achievements and contributions over the past 50 some years.1.Smith D.E. Rowland M. Giacomini K.M. Amidon G.L. Dedication to professor Leslie Z. Benet: 50 years of scientific excellence and still going strong!.Pharm Res. 2012; 29: 2345-2353Crossref PubMed Scopus (3) Google Scholar I hope to add a personal touch to honor Les who is a legend in our field, from my view. Besides being brilliant and insightful, Les is the most dedicated and hardworking person with endless energy, ideas, and enthusiasm in science as well as in service. Undoubtedly, Les has had an extremely busy and successful career; however, he never forgets to put students and teaching as his top priority. He always prepares lectures well, puts on a white lab coat, and delivers the most clear and energetic lecture/speech, explaining complex materials in the most easily understood manner. He truly wants us to learn. Even in recent days, I continue to thoroughly enjoy and learn so much after attending each of Les' lectures at scientific conferences, where he radiates the enthusiasm of teaching the world and delivering innovative concepts. Les quickly recognizes each student's strength or weakness; he gave some of us independence and freedom to explore our research interests, whereas others worked on more well-defined projects. Whatever the case, he provided unwavering support, guidance and resources for us to achieve our goals— and his too. In addition, his discipline, diligence, and perseverance in pursuing research, and what he believes in, has set direct examples for us to follow. Personally, Les' mentoring has been most influential in my development as a scientist, especially in terms of thought process, scientific rigor, integrity, ability to integrate, extrapolate, and pay attention to anomaly or correlation, and importantly, to maintain curiosity and confidence. Les includes his graduate students and postdoctoral fellows as his extended family and he genuinely cares about us professionally and personally, even long after we have graduated. Each year, Les invites us to dinner, either to his house (while as a student) or at the AAPS annual convention, as a venue to share what's happening in his lab, life, and family; hearing updates about our career and life; and fostering alumni networking and collaboration. This big happy family reunion has been one of the highlights of attending the annual AAPS convention year after year, and is all because of Les' generosity and passion for giving and caring. I respect Les for being hardworking, forthright and standing up for the right things without reservation or self interests. No matter how busy he is, we can count on his help and support. Many of Les' students have now retired, but he is still going strong. No doubt, the pharmaceutical world will continuously benefit from Les, an ever-lasting scientist and teacher for centuries. I truly value the life experience and fortune of having studied under Dr. Benet, and knowing Les personally, as a hero and a friend. Les is supremely guided by ethics. He is particularly clear and articulate when it comes to accepting funding. In particular, Les knows when to say no thank you to a funder or philanthropist because the conditions that come with the money are unacceptable. This is a very rare ability in our world today. Les' science is not just in the lab—that would be ordinary. Les' science is out in our big world—the real world. Les works to explain how the world works and why. He continually examines it. He does this as a teacher—so that he can simplify our complex world for others. This work has led to changes in regulations, and in the way we do drug development. Les readily admits when he is wrong. He is bold with the generation of hypotheses, and even more bold with his opinions. When he is wrong, he says so, loudly and clearly. This makes him an exceptional role model. Les is vibrant, healthy, and very alive. He is usually smiling, and full of laughter. He is a happy man. Although he works hard and long, he has always balanced work and the other parts of his abundant life. The choice of Carol as his life partner was the best decision he ever made. Les Benet and I started our scientific careers in the 1960s, and we conducted research in similar areas. However, early in my career, I decided to become a college dean. A few years later, Les mentioned to me that he had decided not to accept any deanship offers, because he saw how it “screwed up” my once promising scientific career. Actually, with his abilities, Les would have been a great dean. However, history has shown that he made the correct judgment. In my opinion, Les has been the most important pharmaceutical scientist worldwide over the past 50 years. Through his original research and leadership, he has influenced the quality and, importantly, the culture of the pharmaceutical sciences throughout the world! Quite an accomplishment for a person that started out wanting to write poetry. To Les, my unofficial mentor. I am privileged to see the personal side of Prof. Benet. Most notable is the strong bonds he maintains with his former students and associates, the advocacy role he has played on behalf of pharmacy and pharmaceutical sciences, and his selflessness in grooming future leaders in their chosen professional calling. Les genuinely enjoys the intellectual challenge of discovery. This mindset underpins his chain of game changing concepts that are destined to transform drug delivery and therapeutics. He is a master of not only filling gaps in knowledge, but also in culture, nationalities, and disciplines. Two Haiku's to Dr. Les Benet. PK PD beLes is more teaching us allPrinciples so rare Dr. Leslie Benet has been such an important part of my own learning and understanding of pharmacokinetics and pharmacodynamics. I consider myself to be so very fortunate to have developed these skills and knowledge and to have been taught and led along the way by the grand master of the field, Dr. Les Benet. His tutelage and mentorship started during my graduate education in the 1970s when Les visited the University of Michigan where he had rigorous and formative interactions with my major professor, the late Dr. John G. Wagner. As was common in those days, there were many hotly debated and divergent viewpoints and opinions about various aspects of fundamental PK and PD properties and relationships. Although being a strong debater and skillful intellectual of these topics, Les always demonstrated a great respect even for those with whom he might heatedly argue. For Les, it always appeared to be about the science and best physiological and pharmacological underpinning of the argument, and not about “winning” or always having to be right. However, we all know that Les was never “wrong”—well at least very infrequently. These were the formative years of the fundamental PK/PD principles that we now accept as proven theorems and the foundational aspects of drug disposition and drug action. However, Dr. Benet's contributions to better understand and define the principles of PK/PD did not stop there for these have exploded in countless dimensions through more than four decades of academic research and scientific writing. Many outstanding PK/PD contributions to science will forever be attributed to just a few select individuals, among which Dr. Les Benet is chief. Leader teacher friendOpening eyes to the truthAchievements he shares Thus, my respect and depth of gratitude to Dr. Les Benet are more than I can simply express. Nonetheless, it is clear that we are all grateful to Les for his many contributions. My sincere best wishes and abundant appreciation to Dr. Benet for being a leader, a teacher, a mentor, and a friend helping us all make greater achievements in life than we ever dreamed possible. It is a wonderful feeling to be associated with Prof. Les Benet, a great giant in the field of Pharmacokinetics. My association with Les is as a scientific colleague, AAPS colleague, and professional mentor. I recall the days when Les had just created AAPS. During the meeting he would stop by and announce with great enthusiasm the continuous increase in membership numbers. That was incredible. I have interacted with Les over several years, but more so lately as a part of AAPS and FIP “outreach activities,” providing education to the scientists. We have traveled together for International Regulatory Science Workshops around the globe. Les has been always supportive, and willing to travel if his schedule/calendar permits. One thing that amazes me is he keeps a tab on every conference/meeting he has attended and can pull out the information in a minute! It is fun to interact and travel with him. It is hard to believe that I have known Leslie for 45 years, almost all my entire professional life. During this time, I have had the honor and pleasure of sharing many, many moments, both scientifically and personally, with this unique and special person, who is warm, generous, ever curious, always committed, and who has had such a profound impact on the pharmaceutical sciences, both nationally and internationally, and on the profession of pharmacy, and beyond. He is a true leader and innovator, who commands respect and admiration. He has made great contributions during his long and illustrious career, but I am sure that there are still more to come. An inspiration to all. Leslie Z. Benet,Our chief championin the pharmaceutical sciences;over 50 yearshe led the wayfrom descriptive to conceptual,from mechanistic to translational,from clinical to practice,and the full cycle in reverse.Overwhelming in advanced thinking,prolific in research output,legendary in expressing views and giving lectures,almost intimidating in providing guidance,most likeable in guiding staff and students,unsurpassed in global recognition,by academia and industry alike,as well as among the regulators,and patients as the ultimate beneficiaries.Les, also as a very dear friend and colleague.We are proud to have him as our heroand chief champion. Les has been my mentor in many aspects—a great inspiration for research and outstanding leadership in scientific societies, and a personal role model for his unfaltering behavior. Normal words cannot adequately express what a positive influence he has had on me and how much his mentoring has done for me and the wider scientific community. Therefore, I decided to fall back on writing a Tanka, which is a traditional form of Japanese poetry to capture the essence of Les and his unwavering support (Fig. 1). Les, we honor you with our expressions of gratitude and perspectives on your “Contributions over Time.” Thank you for your leadership, your vision for the pharmaceutical sciences, your endless encouragement, and most of all, for your boundless zeal that has inspired all of us!