Current Drug Metabolism, Vol. 1, No. 3, 2000
Toxicokinetics
in Drug Development: An Overview of Toxicokinetic Application in the
Development of PNU-101017, an Anxiolytic Drug Candidate. Pp. 243-254.
W.Z. Zhong, M.G. Williams, D.G. Branstetter
Recent Advances in Biotransformation of CNS and Cardiovascular Agents. Pp. 255-270.
W.N. Wu and
L.A. McKown
Fluorine
Nuclear Magnetic Resonance, a Privileged Tool for Metabolic Studies of
Fluoropyrimidine Drugs. Pp. 271-303.
Robert
Martino, Myriam Malet-Martino, Véronique Gilard
[Back to top] Early ADME in Support of Drug Discovery: The Role of Metabolic Stability Studies.
The area of Drug Discovery has undergone an amazing evolution in the past decade. This evolution is typified by the development of automated combinatorial synthesis and high throughput pharmacological testing. This, in turn, has lead to the ability to create and mine extensive databases and then model this new information. The overall result is a substantial increase in the rate of target identification, generation of new leads, and finally, optimization of those leads into clinical candidates.
ADME studies have always played a critical role in helping to optimize the pharmacokinetic (PK) properties of new drugs thereby increasing their success rate. As a consequence of the increased throughput of drug discovery, ADME studies have evolved to keep pace. These so-called “early ADME” studies, are characterized by parallel processing and higher throughput than before.
A primary concern of medicinal chemists is to design molecules that will have not only the desired activity, but also suitable potency and duration of action, which is influenced by pharmacokinetic properties such as bioavailability and half-life. This article focuses on a particular subset of eADME studies known as “metabolic stability”, which can be an important contributor for a good pharmacokinetic profile. Metabolic stability studies represent the adaptation of more complex metabolism rate studies to a minimized system suitable for parallel processing of large numbers of compounds.
The theoretical basis for metabolic stability lies in its relationship to the concept of metabolic intrinsic clearance. Typical metabolic stability protocols are discussed with respect to their relation to drug design. How metabolic stability studies have evolved to keep pace with advances in drug discovery is also discussed. Several case studies of the role of metabolic stability in drug design over the past few years are summarized to exemplify the utility of this kind of study. Finally, future trends in drug metabolism and analytical chemistry and how they may influence metabolic stability studies are reviewed.
[Back to
top] Toxicokinetics in Drug
Development: An Overview of Toxicokinetic Application in the Development of
PNU-101017, an Anxiolytic Drug Candidate.
The importance of toxicokinetics in the drug development has been identified in the last decade. The main objectives of toxicokinetics in general are to define the drug bioavailability, dose proportionality, gender differences, and species differences in pharmacokinetics and metabolism, from which the target organ toxicity can be predicted and the safety doses in the first human clinical trial can be established. Toxicokinetic studies may also serve as a tool for the toxicologic pathologist in understanding models used for predicting and assessing drug-related toxic response. Toxicokinetics/toxicodynamics are critical to investigating the toxicological mechanism and understanding the comparative toxicity between animals and humans. This report presents an overview of the application of toxicokinetics and its impact in the drug development of PNU-101017, a drug candidate for the treatment of anxioety. Serial specifically designed toxicokinetic studies identified a steep dose-response relationship between the clinical signs and PNU-101017 serum or CSF concentrations, characterized the centrally mediated respiratory depression as the toxicity leading to the lethality, and demonstrated marked species differences in the sensitivity to the toxic effects. These findings lead to a termination of PNU-101017 development due to the safety concern in humans.
[Back to
top] Recent Advances in
Biotransformation of CNS and Cardiovascular Agents.
Compound biotransformation is a very important research area
for drug discovery and development. In this review, publications from the
metabolism studies of ten compounds, seven CNS and three cardiovascular agents,
from the Johnson & Johnson Corp. were reviewed. The seven CNS compounds
are: three antipsychotic agents, mazapertine (arypiperazine analog), RWJ-46344
(arypiperidine analog) and risperidone (aryisoxazole-piperidine analog), one
antidepressant, etoperidone (arypiperazine analog), one anxiolytic agent,
fenobam (aryimidazole urea analog), one muscle relaxant, xilobam
(pyrrolidinylidene urea analog), and one antiepileptic agent, topiramate
(fructopyranose sulfamate analog). The three cardiovascular agents are: two
arylalkylamine calcium channel blockers, bepridil and RWJ-26240, and one
thioindolaminidine antianginal agent, RWJ-34130. Other antipsychotic and antidepressant
agents with similar analogs (ziprasidone, trazodone and nefazodone) as well as
other similar analogs of calcium channel blockers (verapamil) are discussed. In
this article, excretion and metabolism (in vitro, in vivo) of compounds are
reviewed from the CNS agents to the cardiovascular agents, including structures
of parent compounds, their metabolites, metabolic pathways, and methods for the
isolation, profiling, quantification and structural identification of unchanged
compounds and metabolites. Pharmacological activities of parent compounds and
their metabolites are also briefly discussed.
[Back to top] Fluorine Nuclear Magnetic Resonance, a Privileged Tool for Metabolic Studies of Fluoropyrimidine Drugs.
Fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopy provides a highly specific tool for identifying fluorine-containing drugs and their metabolites in biological media. This article focuses on the application of 19F NMR to the metabolic studies of fluoropyrimidine drugs in clinical use. The value and difficulties encountered in investigations on drug metabolism are first discussed. The metabolism and disposition studies of the anticancer drug 5-fluorouracil, the mainstay of antimetabolite treatment for solid tumors, and its prodrugs, doxifluridine and capecitabine, are then extensively reviewed. The studies dealing with the antimycotic agent, 5-fluorocytosine, as well as the novel anticancer drug, gemcitabine, are also considered. From in vitro (biofluids or tissue extracts) 19F NMR analysis, seven new metabolites of 5-fluorouracil, doxifluridine, capecitabine and 5-fluorocytosine were identified. Except two, they were only detected using this technique. This emphasizes the high analytical potential of in vitro 19F NMR. In vivo 19F NMR is non-invasive and thus allows the quantitative monitoring of the metabolism of 5-fluorouracil in the target tissue, e.g. the tumor, as well as its biodistribution. Another promising application is its ability to estimate the level of yeast cytosine deaminase gene expression in human tumors from the quantitative monitoring of 5-fluorouracil formation from the non-cytotoxic drug 5-fluorocytosine. Notwithstanding these successes, the limited sensitivity and spectral resolution of 19F NMR precludes its extensive applicability to all the fluorinated drugs.