Julius Axelrod (1912–2004)
Andrew P. Wickens in Key Thinkers in Neuroscience, 2018
Julius Axelrod was a pharmacologist who discovered that certain neurotransmitters such as noradrenaline and serotonin are inactivated through the reuptake into presynaptic nerve terminals – a discovery paving the way for the development of modern antidepressant drugs. He developed a simple assay for measuring aniline in urine and plasma, and even took high doses of acetanilide itself so he could detect aniline in his own urine. He had discovered a family of microsomal enzymes responsible for many aspects of drug metabolism, which later became known as the cytochrome P450 group – now recognised as the most important enzymes in phase I metabolism in mammals. He realised that the release of melatonin followed a circadian pattern and that its rhythmicity persisted when the animals were placed in constant darkness, although abolished in constant light. Unlike many scientists, Axelrod's extraordinary discoveries had come from a small laboratory that normally only employed no more than three or four scientists.
Pharmacokinetic determinants of clinical activity
Adam Doble, Ian L Martin, David Nutt in Calming the Brain: Benzodiazepines and related drugs from laboratory to clinic, 2020
The formation and persistence of desmethyldiazepam in the organism has several important repercussions in clinical practice. The pharmacokinetic profiles of diazepam and desmethyldiazepam after single administration are illustrated. Oxazolam is another benzodiazepine devoid of activity at the benzodiazepine binding site that is metabolised in vivo to desmethyldiazepam. The primary determinant of the efficacy of benzodiazepines is the concentration achieved in the plasma of parent drug and/or active metabolites. For anxiolytic benzodiazepines, rate of absorption is of little importance compared with achieving stable plasma levels after repeated administration. Elimination half-lives are also critical parameters for hypnotic benzodiazepines. The vast majority of benzodiazepines are metabolised in the liver by Type I oxidation involving cytochrome P450 enzymes. Certain benzodiazepines are converted by hepatic metabolism into other species that are responsible for exerting their biological effects. The effects of benzodiazepines can change with the age of the patient to whom they are administered.
Background for Chemists
Jack P. Uetrecht, William Trager in Drug Metabolism, 2007
At a fundamental level, the importance of concentration and elaborating the parameters that govern the concentration and lifetime of a drug in vivo, from its adsorption, accumulation, and elimination, has been the focus of the study of the field of pharmacokinetics and its parent discipline biopharmaceutics. Bioavailability is a term used to indicate both the rate and fraction of an administered drug that reaches the general circulation intact. The preeminent variable governing bioavailability is the mode of administration. As a drug is absorbed and enters the general circulation, its concentration in the blood begins to rise. Experimentally, for ease of analysis a drug’s concentration in blood is measured as its concentration in plasma, i.e., a blood sample is taken, centrifuged to precipitate the red blood cells, and then the supernatant or plasma is analyzed for drug concentration. A special case of noncompetitive inhibition that is sometimes seen in drug metabolism studies, particularly with cytochrome P450-catalyzed reactions, is suicide inhibition.
Presence Of Hexobarbital in Primary Cultures of Rat Hepatocytes Maintains Cytochrome P-450 Levels and Drug Metabolizing Enzyme Activities
Published in Drug and Chemical Toxicology, 1988
H. M. Kim, J. R. Ha, S. K. Park, K. H. Yang
Addition of hexobarbital (1 mM) to the culture medium of rat hepatocytes protected against the rapid decline in the level of cytochrome P-450 and the activities of various drug metabolizing enzymes. While the hepatocytes cultured for 72 hr without hexobarbital had only 30% of their original level of cytochrome P-450, the cells maintained with hexobarbital had 75% of the initial level of the hemoprotein. After 72 hr in culture, the activities of aminopyrine N-demethylase and biphenyl 4-hydroxylase were 22-24% of the original rate for the nontreated cells and 73–78% for the hexobarbital treated cells. The activities of 7-ethoxycoumarin 0-deethylase and aryl hydrocarbon hydroxylase in the cultures of treated cells were even higher than those of the freshly isolated hepatocytes. Additions of other substrates of hepatic mixed function oxidase to the culture medium did not protect against the loss of cytochrome P-450 and enzyme activities.
Plasma high-density lipoprotein cholesterol and hepatic cytochrome P-450 concentrations in epileptics undergoing anticonvulsant treatment
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 1980
P. V. Luoma, E. A. Sotaniemi, R. O. Pelkonen, V. V. Myllylä
Relation of plasma high-density lipoprotein (HDL) cholesterol concentration to hepatic microsomal enzyme activity in eighteen epileptics with diagnostic liver biopsy was investigated, the cytochrome P-450 content in biopsy samples being used to reflect the liver enzyme activity. A significant correlation (r = 0.67, P
Modulation of Human T-Lymphocyte Plasma Membrane Ca +2 Permeability by Imidazole Antimycotics
Published in Immunopharmacology and Immunotoxicology, 1996
Edmund H. Hornstein, Dimitrios Vassilopoulos, Donald E. Thomas, Fred K. Friedman, George C. Tsokos
The role of cytochrome P-450 in the regulation of plasma membrane Ca+2 permeability of human peripheral T-lymphocytes by intracellular Ca+2 was examined. We assessed the effect of imidazole inhibitors of cytochrome P-450 on the intracytoplasmic free Ca+2 ([Ca+2]i) response generated using the microsomal ATPase inhibitor thapsigargin (THG) to deplete the intracellular Ca+2 stores. Econazole, miconazole and clotrimazole dramatically inhibited the THG mediated increase in [Ca+2]i and indud an increase in [Ca+2]i themselves. This inhibitory effect was previously observed in other cell systems and was attributed to inhibition of cytochrome P-450 by these agents. However, we evaluated a variety of structurally dissimilar P-450 inhibitors and found that none affected [Ca+2]i, indicating that the mechanism of imidazole action does not involve P-450.