Towards Safer and More Predictable Drug Treatment – Reflections from Studies of the First BCPT Prize Awardee

Abstract

This MiniReview is a personal recollection of selected research topics, which the author in collaboration with colleagues has studied, aiming to improve the predictability of drug therapy. In early studies, we found bi-and trivalent cations to reduce the absorption of various tetracyclines and fluoroquinolones. Certain antacids elevated the bioavailability of some nonsteroidal anti-inflammatory drugs and sulphonylureas. Various brands of phenytoin tablets revealed great differences in their bioavailability, causing clinical consequences. Numerous factors affecting the antidotal effect of activated charcoal were also studied, with charcoal compared to other gastrointestinal decontamination methods, including ipecac and gastric lavage. Effect of age and diseases on the pharmacokinetics of drugs was a research topic. Acute sotalol intoxications revealed its QT-prolonging properties, and even small mixed overdoses of moclobemide with serotonergic drugs proved fatal. Itraconazole and other potent inhibitors of CYP3A4 could drastically increase exposure to drugs like midazolam, triazolam, buspirone, lovastatin, simvastatin and oxycodone, whereas rifampicin greatly reduced their plasma concentrations. A change from potent inhibition to induction caused a 400-fold change in the exposure to oral midazolam. CYP2C8 was revealed to be crucial in the metabolism and interactions of several drugs. Many interactions affecting statins are CYP3A4-mediated, but transporters are important in certain interactions. Tizanidine is very susceptible to CYP1A2 inhibition. Fruit juices such as grapefruit juice can raise or lower exposure to different drugs. Both drug interactions and pharmacogenetics can modify the activity of cell membrane transporters and cause variability in the pharmacokinetics of and response to their substrate drugs.This MiniReview is a personal recollection of certain research projects in which the author has participated in collaboration with many colleagues in the last 45 years. Without clever doctoral students and brilliant co-supervisors, many of these studies would not have been possible. I am most grateful to all these colleagues in Finland and abroad for our very smooth and fruitful cooperation. This MiniReview also reflects some of the topics that have been relevant in clinical pharmacological research during these decades. It also gives some hints as to the challenges that researchers sometimes may face if they observe adverse drug interactions or other potentially negative aspects of a drug. Interference with the Absorption Tetracyclines and FluoroquinolonesMany of the patients suffering from prolonged infections and having a subnormal haemoglobin level were, in the 1960s and early 1970s, given tetracyclines and iron. Nowadays, it is well known that infectious anaemia is not an iron-deficient anaemia and that iron administration may even have a negative effect on recovery. As there were some reports that bi-and trivalent cations could form insoluble chelates with tetracyclines, we decided to stud...

Role of Cytochrome P450 2C8 in Drug Metabolism and Interactions

“…Role of CYP2C8 in Drug Metabolism and Interactions or incorrect product information regarding their interaction potential (Neuvonen, 2012). One example is the leukotriene receptor antagonist montelukast.…”

Drug‐Related Inadvertent Deaths in a University Hospital – A Declining Trend

“…However, most drugs have their pros and cons. Despite continuous attempts towards safer and more predictable drug treatment, drugs also have adverse effects . An adverse drug reaction (ADR) is by the WHO definition ‘a response to a drug that is noxious and unintended and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function’ .…”

Nifedipine versus Terbutaline, Tocolytic Effectiveness and Maternal and Neonatal Adverse Effects: A Randomized, Controlled Pilot Trial

“…In many countries, these considerations led to the withdrawal from the market of nifedipine's quick release presentation [26]. Considering possible under-reporting of adverse effects, authors recommend precaution, particularly in women with cardiovascular morbidity [2,44,45].…”