Progress in clinical pharmacology over the last 20 years

Abstract

The late 1950s and early 1960s witnessed a dramatic change in the practice of medicine. At this time many drugs were introduced into the clinic which for the first time allowed the effective treatment of many common diseases such as hypertension, angina pectoris, depression, schizophrenia, carcinomas and leukaemias to name only a few. Right from the beginning of modern drug therapy, it was observed that there was substantial variability among patients both in therapeutic efficacy and the occurrence of side-effects. The realization that dose was a poor predictor of therapeutic response raised the curiosity of clinicians and pharmacologists in elucidating the mechanisms responsible. This was the starting point for the development of clinical pharmacology. Of great importance for clinical pharmacology was the work carried out by the groups of R. T. Williams at St Mary's Hospital and B. B. Brodie in the Laboratory of Chemical Pharmacology at the NIH who pioneered the work on drug metabolism. The discovery of drug-metabolizing enzymes and realizing that their activity determined the rate at which drugs were eliminated from the body was instrumental for our understanding of why patients respond differently to the same dose of a drug. In a number of elegant studies, B. B. Brodie and coworkers showed that species differences in the duration of hexobarbitone action after administration of the same dose were not due to differences in sensitivity but a consequence of pronounced species differences in the rate of biotransformation of hexobarbitone. Moreover, he showed that the blood concentration at the time of awakening was very similar among the various species and in man. It is still worth reading his famous Toral Sollmann Award lecture Of Mice, Microsomes and Man at the ASPET Meeting (August 13, 1963). In this lecture, many principles that can account for variability in drug response between animals and humans were put forward. The concept that drug effects are not related to the dose administered but rather the plasma concentration achieved, and that in analogy to species differences, patient-to-patient variability in response can be explained by different plasma concentrations, was instrumental for clinical pharmacology.Rather than giving a detailed account on the progress being made, I would like to focus on Alasdair Breckenridge's contribution to the field of drug metabolism. It is in the area of drug metabolism and especially in understanding the various factors that could affect the activity of drug-metabolizing enzymes where Alasdair Breckenridge has made substantial contributions to clinical pharmacology throughout his professional career. His interest was not restricted to the experimental findings but to explore the consequences of his results for drug action and side-effects in patients. It is a persistent feature of his work that observation of a clinical problem led him to carry out experimental work to understand the mechanisms responsible and then to test the hypothesis generated in his laboratory experi...

Clinical Pharmacology Education – The Decade Ahead

“…Clinical pharmacology training programs have changed markedly in recent decades, with substantial advances in our understanding of the processes that govern drug absorption, distribution, metabolism, and elimination. 1 These programs are based in schools of medicine and pharmacy, and carry many names, including "experimental therapeutics", "pharmacotherapy", "translational science" as well as traditional "clinical pharmacology". Today's clinical pharmacologists are trained in more diverse and collaborative environments by both clinicians and scientists.…”

Klinik Farmakoloji: Türkiye Açısından Geleceğe Yönelik Bir Perspektif

“…Hem temel hem de klinik farmakologlar ve klinisyenler terapötik etkililikte ve de yan etkilerin ortaya çıkmasında hastalar arasında anlamlı farklılıklar olduğunu tespit etmeye başlamışlar ve bu bireyler arası farklılığın açıklanmasında ilaç metabolizmasının öneminin farkına varmışlardır 3,7 . İlaç etkisinde dozdan ziyade kandaki ilaç konsantrasyonunun belirleyici olması ve hastalar arasındaki varyasyonun kandaki ilaç konsantrasyonlarındaki farklılıklardan kaynaklandığı konsepti klinik farmakoloji için enstrümental bir durum yaratmıştır 7 . Aslında, bu konu geliştikçe temel çalışmaların birçoğu biyokimya ve moleküler biyoloji laboratuvarlarında yapılmıştır 3 .…”

“…Brodie'nin NIH'taki laboratuvarı dünyanın ilaç metabolizma araştırma merkezi haline gelmiştir 3 . Buradaki bilim adamları ilk defa ilaç metabolizmasının inhibisyonu ve indüksiyonunu, sorumlu enzimlerin saflaştırılmasını ve metabolitlerin toksisitedeki önemini göstermişlerdir 3,7 . Çığır açan bir gelişme 1962 yılında sitokrom P450 enzimi ve onun izoformlarının varlığının keşfi olmuştur 3 .…”

“…Çığır açan bir gelişme 1962 yılında sitokrom P450 enzimi ve onun izoformlarının varlığının keşfi olmuştur 3 . Bin dokuz yüz seksenlerle birlikte ise ilaçların kiralitesinin de gerek etkide gerekse dispozisyonda önemli olduğu fark edilmiş ve başta varfarin olmak üzere R ve S enantiomerlerin kişiler arası farklılıklardan sorumlu olduğu keşfedilmiştir 7 .…”

“…Benzer olarak karaciğere ek olarak presistemik eliminasyona bağırsak duvarının da katkıda bulunduğu ve absorbsiyonda aktif transportunda rol alabileceği görülmüştür 7 .…”