Current Drug Metabolism, Volume 3, No. 3, 2002
Isothiocyanates as Cancer Chemopreventive Agents: Their Biological Activities and Metabolism in Rodents and Humans Pp.233-255
C. Clifford Conaway, Yang-ming Yang, and Fung-Lung Chung
Evaluation of Drug Interactions with P-Glycoprotein in Drug Discovery: In Vitro Assessment of the Potential for Drug-Drug Interactions with P-Glycoprotein Pp.257-273
Jerome H. Hochman, Masayo Yamazaki, Tomoyuki Ohe,and Jiunn H. Lin
Review: Metabolism of Immunosuppressant Drugs Pp.275-287
Patrick Kelly and Barry D. Kahan
Cytochrome P450 Pharmacogenetics in Drug Development: In Vitro Studies and Clinical Consequences Pp.289-309
A. David Rodrigues and Thomas H. Rushmore
Mutagenesis by Environmental Pollutants and Bio-Monitoring of Environmental Mutagens Pp.311-319
H. Sato and Y. Aoki
Catechol-O-Methyltransferase (COMT)-Mediated Methylation Metabolism of Endogenous Bioactive Catechols and Modulation by Endobiotics and Xenobiotics: Importance in Pathophysiology and Pathogenesis 321-349
Bao Ting Zhu
[Back to top] Isothiocyanates as Cancer Chemopreventive Agents: Their Biological Activities and Metabolism in Rodents and Humans
C. Clifford Conaway, Yang-ming Yang, and Fung-Lung
Chung
Isothiocyanates (ITCs) are a group of naturally occurring
compounds that occur as thioglucoside conjugates, termed glucosinolates, in
plants and cruciferous vegetables such as watercress, Brussels sprouts,
broccoli, cabbage, kai choi, kale, horseradish, radish and turnip. ITCs inhibit
the development of tumors in many of the experimental models investigated, and
are being investigated as possible chemopreventive agents for specific human
cancers. The goal of this review is to provide a mechanistic understanding for
the biological activities of ITCs and to relate the metabolism of ITCs to their
action as chemopreventive agents. In vivo animal studies have been conducted to
address issues of tissue disposition, pharmacokinetics, and metabolism of ITCs.
Methods for analysis of ITCs and their metabolites in urine and plasma have
been developed. The metabolism of several naturally occurring ITCs as
constituents of foodstuffs or as drugs has also been investigated in human
studies. Finally, based on recent epidemiological studies, the role of dietary
consumption of vegetables containing ITCs in prevention of human cancers and
human cancer susceptibility is discussed.
[Back to top] Evaluation of Drug Interactions with P-Glycoprotein in Drug Discovery: In Vitro Assessment of the Potential for Drug-Drug Interactions with P-Glycoprotein
Jerome H. Hochman, Masayo Yamazaki, Tomoyuki Ohe,and
Jiunn H. Lin
The pharmacological effects of a drug are highly dependent on the absorption, metabolism, elimination, and distribution of the drug. In the past few years it has become apparent that transport proteins play a major role in regulating the distribution, elimination and metabolism of some drugs. As a consequence of our new understanding of the influence of transport proteins on the pharmacokinetic and pharmacodynamic behavior of drugs, increasing attention has been focused on the potential for drug-drug interactions arising from interactions with drug transport proteins. The efflux transporter P-glycoprotein (P-gp) has received the most attention with regard to its role in restricting drug absorption and distribution and as a potential source for variability in drug pharmacokinetics and pharmacodynamics. This review will focus on the evaluation of drug candidates to assess the potential for drug interactions at the level of P-gp. We will discuss the role of P-gp in drug disposition, the biochemistry of P-gp efflux as it relates to model systems to study drug interactions with P-gp, and the implementation of P-gp assay models within the drug discovery process.
[Back to top] Review: Metabolism of Immunosuppressant Drugs
Patrick Kelly and Barry D. Kahan
Pharmacokinetic concepts provide a basis for individualization of drug therapy to optimize outcomes of the critical-dose drugs cyclosporine (CsA), tacrolimus (TRL), sirolimus (SRL), and mycophenolate mofetil (MMF). The therapeutic range of a drug—defined as the concentrations at which the desired pharmacologic effect is produced without adverse effects in most patients—is difficult to achieve given the significant inter-and intrapatient variability of the effects of a given concentration of therapeutic agents. Because of the highly variable rates of absorption of immunosuppressive agents and clinical responses to given concentrations in transplant recipients, individualization of drug regimens by using therapeutic drug monitoring (TDM) is essential to optimize pharmacotherapy
Assessing proclivity for acute rejection episodes in transplant recipients currently is attempted by estimating drug exposure using the area under the time-concentration curve (AUC) for MMF and the average concentration (Cav, the quotient of the AUC and the dosing interval) for CsA. These studies have revealed that low oral bioavailability was a more important predictor of rejection than was a rapid clearance rate. In addition, the degree of intra-individual variability of AUC values correlated with the development of chronic rejection in renal transplant recipients.
Similarly, TDM of MMF requires AUC determinations. Low mycophenolic acid (MPA) exposure, as estimated by the AUC, demonstrates a significant association with an increased risk of an acute renal transplant rejection episode. The AUC0-2 estimate of MPA shows good agreement with the 12-hr AUC estimate from samples obtained during the entire dosing interval.
In contrast, trough levels are utilized during treatment with TRL or SRL, potent new immunosuppressive agents that display a pleiotropic array of side effects. Standard body measures, including weight and body mass index, poorly predict the concentration of SRL in whole blood. Large inter- and intra-individual differences displayed in patients also could not be predicted by demographic features or by laboratory parameters. When SRL is given with other immunosuppressive agents such as CsA, which shares with SRL mutual microsomal metabolism by the cytochrome P450 3A system, pharmacokinetic interactions occur, especially when the agents are administered concomitantly.
Because of the critical-dose nature of most of the recent
generation of immunosuppressive agents, therapeutic drug monitoring is becoming
increasingly important in the selection of doses and treatment regimens.
[Back to top] Cytochrome P450 Pharmacogenetics in Drug Development: In Vitro Studies and Clinical Consequences
A. David Rodrigues and Thomas H. Rushmore
Members of the human cytochrome P450 (CYP) superfamily play a role in the metabolism of many drugs and several of them, CYP2D6, CYP2C9 and CYP2C19, have been shown to be polymorphic as a result of single nucleotide polymorphisms (SNPs), gene deletions, and gene duplications. These polymorphisms can impact the pharmacokinetics (PK), metabolism, safety and efficacy of drugs, and because of the availability of automation, genotyped human tissue, recombinant CYP preparations (rCYPs) and reagents, most pharmaceutical companies have increasingly screened out compounds that are metabolized solely by polymorphic CYPs. In the absence of suitable animal models, it has been widely accepted that such in vitro data are useful because one can obtain information prior to dosing in man and select the most appropriate clinical studies with prospectively genotyped and phenotyped subjects. Overall, current trends in the industry have been fueled by increased managed healthcare, the desire to minimize the need for therapeutic drug monitoring and CYP genotyping in medical practice, and a very competitive market place. In the past, such paradigms have not been as influential and there are numerous examples of marketed drugs that are metabolized by polymorphic CYPs.
[Back to top] Mutagenesis by Environmental Pollutants and Bio-Monitoring of Environmental Mutagens
H. Sato and Y. Aoki
There is serious concern about the adverse effects of environmental pollutants on human health. Various mutagens, which pollute air, water, and food, possibly induce mutations in humans, and are suspected of causing cancer. Environmental mutagens, such as polycyclic aromatic hydrocarbons (PAH) and heterocyclic amines are known to bind to nucleotides, resulting in the formation of DNA adducts. Some DNA adducts are fixed as mutations through replication of DNA. Reactive oxygen species generated by pollutants also induce the formation of DNA adducts. DNA adducts have been detected as a marker for the exposure of humans and wild life to mutagens.
Because of its high sensitivity the 32P-postlabel-thin layer chromatography (TLC) method is widely used for the analysis of DNA adducts formed by PAH and related bulky compounds. However, new systems are required for detecting mutations induced in genomic DNA in vivo to monitor environmental mutagens. Recently, transgenic animals, in which a target gene for detecting mutations is integrated, have been developed. With these transgenic animals, not only mutant frequency but mutation spectra can be determined.
We review here recent advances in the detection of DNA adducts formed by environmental pollutants and their application for biological monitoring of environmental mutagens. We also discuss transgenic animals as important tools for evaluating the total mutagenic potential of environmental chemicals.
[Back to top] Catechol-O-Methyltransferase (COMT)-Mediated Methylation Metabolism of Endogenous Bioactive Catechols and Modulation by Endobiotics and Xenobiotics: Importance in Pathophysiology and Pathogenesis
Bao Ting Zhu
The metabolic O-methylation of endogenous catecholamines and other catechols catalyzed by catechol-O-methyltransferase (COMT; EC 2.1.1.6) was first described by Dr. Julix Axelrod and his colleagues almost half a century ago. In the past several years, research interest in this catechol-metabolizing system has been renewed because of its potential pathophysiological and pathogenic significance in estrogen-induced hormonal cancers, in the development of degenerative brain disorders, as well as in the development of cardiovascular diseases. In this review paper, I provide a brief overview of the COMT metabolic system, with particular attentions being paid to the following three areas: (i) the regulation of this catechol-metabolizing system by endogenous regulatory factors (mainly S-adenosyl-L-homocysteine and homocysteine) as well as by exogenous factors such as dietary phytochemicals; (ii) decreased metabolic O-methylation of endogenous catecholamines as an important risk factor for the development of neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases in the elderly and also as a risk factor for the development of a variety of cardiovascular diseases; and (iii) the relative importance of the COMT-catalyzed O-methylation metabolism of endogenous catechol estrogens in the causation and prevention of estrogen-induced hormonal cancers. Some unifying hypotheses are also discussed in this paper with the hope that they may provide useful mechanistic insights into our understanding of the biological functions that are associated with this important metabolic system.