Current Drug Metabolism, Volume 5, Number 5, 2004
Contents
Cigarette Smoking, Metabolic Activation and
Carcinogenesis Pp.363-373
Akiyoshi Nishikawa, Yukio Mori, In-Seon Lee,
Takuji Tanaka and Masao Hirose
Biopharmaceutic Classification System: A
Scientific Framework for Pharmacokinetic Optimization in Drug Research Pp.375-388
Manthena V.S. Varma, Sateesh Khandavilli,
Yasvanth Ashokraj, Amit Jain, Anandbabu Dhanikula, Anurag Sood, Narisetty S.
Thomas, Omathanu Pillai,
Pradeep Sharma, Rajesh Gandhi, Shrutidevi Agrawal, Vinod Nair and Ramesh
Panchagnula
Metabonomics: Its Potential as a Tool in
Toxicology for Safety Assessment and Data Integration Pp.389-398
J.L. Griffin and M.E. Bollard
Effect of Growth Factors as Therapeutic Drugs
on Hepatic Metabolism During the Systemic Inflammatory Response Syndrome Pp.399-413
Marc G. Jeschke and David N. Herndon
Therapeutic Drugs that Behave as
Mechanism-Based Inhibitors of Cytochrome P450 3A4 Pp.415-442
Shufeng Zhou, Eli Chan, Lee Yong Lim, Urs A.
Boelsterli, Shu Chuen Li1, Jiancheng Wang, Qiang Zhang, Min Huang, Anlong Xu
Human Hepatocytes in Primary Culture: The
Choice to Investigate Drug Metabolism in Man Pp.443-462
M.J. Gomez-Lechon, M.T. Donato, J.V. Castell
and R. Jover
Abstracts
[Back
to top] Cigarette
Smoking, Metabolic Activation and Carcinogenesis
Akiyoshi Nishikawa, Yukio Mori, In-Seon Lee,
Takuji Tanaka and Masao Hirose
Epidemiologically, it has been suggested that cigarette smoking is closely associated with an increased risk of cancers in various organs such as the lung, oropharynx, stomach, pancreas, liver and colon. Nevertheless, influences of cigarette smoking on experimental tumorigenesis in organs other than the respiratory tract remain to be elucidated. In our experimental studies, it has been shown that cigarette smoke exposure induces hepatic CYP enzymes, especially CYP1A2, in both rats and hamsters, and S9 fraction from their livers exposed to cigarette smoke specifically increases the mutagenicity in Ames assay of various heterocyclic amines (HCAs) contained in cigarette smoke and cooked food, which is in good agreement with the fact that HCAs are principally activated by CYP1A2 to proximate carcinogens. In fact, cigarette smoke exposure enhanced liver carcinogenesis in rats induced by 2-amino-3, 8-dimethylimidazo[4, 5-f]quinoxaline (MeIQx), a major HCA. Furthermore, in our recent study, it was also shown that cigarette smoke exposure induces hepatic CYP2A8 in hamsters, which is homologous to CYP2A6 in human, and hepatic S9 fraction exposed to cigarette smoke increases the mutagenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK), a tobacco specific nitrosamine, which is in line with the fact that NNK is metabolically activated by CYP2A6. Keeping these data, the aim of this review is to discuss any relevancy of modulated metabolic activation by cigarette smoking to cancer risk in human.
[Back
to top] Biopharmaceutic
Classification System: A Scientific Framework for Pharmacokinetic Optimization
in Drug Research
Manthena V.S. Varma, Sateesh Khandavilli,
Yasvanth Ashokraj, Amit Jain, Anandbabu Dhanikula, Anurag Sood, Narisetty S.
Thomas, Omathanu Pillai,
Pradeep Sharma, Rajesh Gandhi, Shrutidevi Agrawal, Vinod Nair and Ramesh
Panchagnula
The tenets of biopharmaceutics, solubility and permeability, are of pivotal importance in new drug discovery and lead optimization due to the dependence of drug absorption and pharmacokinetics on these two properties. A classification system for drugs based on these two fundamental parameters, Biopharmaceutic Classification System (BCS), provides drug designer an opportunity to manipulate structure or physicochemical properties of lead candidates so as to achieve better “deliverability”. Considering the facts for failure of NCEs, drug research, once concentrating on optimizing the efficacy and safety of the leads, dramatically transformed in the past two decades. With the enormous number of molecules being synthesized using combinatorial and parallel synthesis, high throughput methodologies for screening solubility and permeability has gained significant interest in pharmaceutical industry. Ultimate aim of the drug discovery scientist in pharmacokinetic optimization is to tailor the molecules so that they show the features of BCS class I without compromising on pharmacodynamics. Considerations to optimize drug delivery and pharmacokinetics right from the initial stages of drug design propelled need for “High Throughput Pharmaceutics” (HTP). In silico predictions and development of theoretical profiles for solubility and lipophilicity provides structure based biopharmaceutical optimization, while in vitro experimental models (microtitre plate assays and cell cultures) validate the predictions. Thus, biopharmaceutical characterization during drug design and early development helps in early withdrawal of molecules with insurmountable developmental problems associated with pharmacokinetic optimization.
[Back
to top] Metabonomics: Its Potential as a Tool in Toxicology for Safety
Assessment and Data Integration
J.L. Griffin and M.E. Bollard
The functional genomic techniques of transcriptomics and proteomics promise unparalleled global information during the drug development process. However, if these technologies are used in isolation the large multivariate data sets produced are often difficult to interpret, and have the potential of missing key metabolic events (e.g. as a result of experimental noise in the system). To better understand the significance of these megavariate data the temporal changes in phenotype must be described. High resolution 1H NMR spectroscopy used in conjunction with pattern recognition provides one such tool for defining the dynamic phenotype of a cell, organ or organism in terms of a metabolic phenotype. In this review the benefits of this metabonomics/metabolomics approach to problems in toxicology will be discussed. One of the major benefits of this approach is its high throughput nature and cost effectiveness on a per sample basis. Using such a method the consortium for metabonomic toxicology (COMET) are currently investigating ~150 model liver and kidney toxins. This investigation will allow the generation of expert systems where liver and kidney toxicity can be predicted for model drug compounds, providing a new research tool in the field of drug metabolism. The review will also include how metabonomics may be used to investigate co-responses with transcripts and proteins involved in metabolism and stress responses, such as during drug induced fatty liver disease. By using data integration to combine metabolite analysis and gene expression profiling key perturbed metabolic pathways can be identified and used as a tool to investigate drug function.
[Back
to top] Effect of Growth Factors as Therapeutic Drugs on Hepatic Metabolism During
the Systemic Inflammatory Response Syndrome
Marc G. Jeschke and David N. Herndon
Characteristic for critically ill patients is a hypermetabolism and catabolism that is associated with impairment of the structure and function of essential organs, such as the immune system, kidney, peripheral muscles and the liver. The liver-gut-axis, with liver integrity, metabolism and function are crucial for survival of patients suffering from trauma, operations or infections. The hepatic acute phase response represents a cascade of events characterized by the upregulation of acute phase proteins and the downregulation of constitutive hepatic proteins. The goal of the hepatic acute-phase-response, which is mediated by cytokines and signal transcription factors, is to restore homeostasis. However, multiple studies have shown that a sustained or increased acute phase response is detrimental with the uncontrolled and prolonged action of acute phase proteins. The downregulation of constitutive hepatic proteins may further augment these detrimental effects. Research has focused on the attenuation of the inflammatory response using anti-inflammatory agents or antibodies against pro-inflammatory cytokines such as tumor necrosis (TNF), interleukin-1b (IL-1b), or their receptors. These approaches showed promising results in vitro and in animal models; however, when these approaches entered clinical trials it became evident that these promising animal data could not be substantiated in humans. A different approach is to attenuate the inflammatory cascade by the administration of growth factors. Growth factors exert anabolic effects and affect the inflammatory hepatic metabolism. The present review discusses the effect of recombinant human growth hormone, insulin-like growth factor-I, hepatocyte growth factor and insulin on the hepatic metabolism and homeostasis during inflammation and delineates the therapeutic benefit and limitation of growth factor administration in critically ill patients.
[Back
to top] Therapeutic Drugs that Behave as Mechanism-Based Inhibitors of
Cytochrome P450 3A4
Shufeng Zhou, Eli Chan, Lee Yong Lim, Urs A.
Boelsterli, Shu Chuen Li1, Jiancheng Wang, Qiang Zhang, Min Huang, Anlong Xu
Cytochrome P450 (CYP) 3A4 is not only the most abundant isoform in human liver but also metabolizes approximately 60% of the therapeutic drugs. This feature renders CYP3A4 highly susceptible to both reversible and irreversible (mechanism-based) inhibition. The latter is characterized by NADPH-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYPs to reactive metabolites. Mechanism-based inactivation of CYP3A4 by drugs can be due to the chemical modification of the heme, the protein, or both as a result of covalent binding of modified heme to the protein. The clinical pharmacokinetic effect of a CYP3A4 inactivator is a function of its KI, kinact and partition ratio and the synthesis rate of new or replacement enzyme. Predicting drug-drug interactions involving CYP3A4 inactivation is possible when proper pharmacokinetic principles are followed. However, the prediction may become difficult, since the clinical outcomes due to CYP3A4 inactivation depend on many factors associated with the enzyme, drugs and the patients. A number of clinically important drugs have been identified to be mechanism-based CYP3A4 inhibitors. These include antibiotics (e.g. erythromycin and isoniazid), anticancer drugs (e.g. tamoxifen), antidepressants (e.g. fluoxetine and midazolam), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine and verapamil), steroids and their receptor modulators (e.g. gestodene and raloxifene), and some herbal constituents (e.g. bergamottin and glabridin). Compared to reversible inhibition, mechanism-based inhibitors of CYP3A4 more frequently cause unfavorable drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesized CYP3A4 protein. Most CYP3A4 inactivators are also PgP substrates/inhibitors, confounding the in vitro-in vivo extrapolation. Clinicians should have good knowledge on these CYP3A4 inactivators and avoid their combination use.
[Back
to top] Human
Hepatocytes in Primary Culture: The Choice to Investigate Drug Metabolism in
Man
M.J. Gomez-Lechon, M.T. Donato, J.V. Castell
and R. Jover
Different types of hepatic tissue, including whole or split livers from organ donors or waste liver from therapeutic liver resections, are used to prepare human hepatocyte cultures. Characteristics of liver samples from different origins (gender, age, healthy/pathological status, xenobiotic treatment) as sources of human hepatocytes are key factors which notably determine viability and functionality of hepatocytes. The characterisation of the CYP system can be assessed in terms of activity (using specific substrates/inhibitors), protein (antibody analysis) and molecular biology-based mRNA amplification techniques (PCR technology and DNA microarrays). It could reasonably be considered that human hepatocytes reflect the heterogeneity of CYP expression in human liver and is a suitable model for drug metabolism studies. Several key issues need to be addressed at the early stages of drug development to better select drug candidates (metabolic profile and rate, identification of CYPs involved, drug-drug interactions due to enzyme induction/inhibition). The metabolic stability and metabolite profile of new chemicals can be easily investigated by incubating the drugs with fully competent metabolic models like hepatocyte suspensions or 24 h-cultured hepatocytes. CYP inhibitory effects are usually screened in recombinant CYP enzymes or microsomes, however, the actual concentration of substrate and inhibitor available to the CYP enzyme depends on processes missing in subcellular models (transport mechanisms, cytosolic enzymes, binding to intracellular proteins). Since intact cells more closely reflect the environment to which drugs are exposed in the liver, cultured hepatocytes constitute a more predictive model for drug-drug interactions. Screening of CYP inducers cannot be done in microsomes as it requires a cellular system fully capable of expressing CYP genes. Primary hepatocytes are still the unique in vitro model for global examination of inductive potential of drugs (monitored as increases in mRNA content or activity).