Current Drug Metabolism - Volume 11, Issue 1, 2010

The field of drug metabolism has changed dramatically in the past generation. Two of the driving forces are the advances in analytical chemistry and our understanding of the biological systems. With regard to the former, the advances in liquid chromatography-mass spectrometry (LC-MS) are extremely impressive, and the speed of analysis has been increased even more with the recent developments in ultraperformance LC (UPLC). NMR analysis on a sub-microgram scale is not unusual, and the 2-dimensional methods are also very impressive. The biology underlying gene regulation is highly developed, and the recombinant methods have greatly facilitated progress in the field. Today it is common to design discovery and development efforts focused on critical human phenomena from the very start, with animal studies supporting the efficacy and safety efforts.

The present paper is an update of the data on the effects of diseases and environmental factors on the expression and/or activity of human cytochrome P450 (CYP) enzymes and transporters. The data are presented in tabular form (Tables 1 and 2) and are a continuation of previously published summaries on the effects of drugs and other chemicals on CYP enzymes (Rendic, S.; Di Carlo, F. Drug Metab. Rev., 1997, 29(1-2), 413-580., Rendic, S. Drug Metab. Rev., 2002, 34(1-2), 83-448). The collected information presented here is as stated by the cited author(s), and in cases when several references are cited the latest published information is included. Inconsistent results and conclusions obtained by different authors are highlighted, followed by discussion of the major findings. The searchable database is available as an Excel file, for information about file availability contact the corresponding author.

In view of the pivotal role played by the diversity of fatty acid-derived oxy-products in a vast array of physiological processes, precise knowledge about the molecular principles dictating substrate specificity and regioselectivity in P450-catalyzed oxidative attack on the distinctly structured carbon chains of the monocarboxylic acids is of paramount importance. Based on a general, CYP102A1- related construct, the majority of prospective key determinants participating in fatty acid recognition/binding were found to cluster near the distal heme face made up by the helical B', F, G and I tetrad as well as the B'-C interhelical loop and certain β-sheet segments. Most of the contact sites examined show a frequency of conservation <10%, hinting at the requirement of some degree of conformational flexibility. Some decisive elements may also have a function in maintaining active-site integrity, governing substrate access to the catalytic centre, and steering the redox machinery to efficiently promote fatty acid oxidations. Physico-chemical factors imposing constraints on orientation of the fatty acid molecules towards the iron-oxene core focus on the variably expressed polarity profile of the diverse docking regions and bulkiness of critical amino acid side chains, acting as selectivity filters for the substrate homologues. Also, dynamic fluctuations of certain contact sites located in the distal backbone of P450s may impact fatty acid positioning. Genetic engineering to introduce versatile properties into fatty acid hydroxylases may give an impetus to biotechnological exploitation of the tailored enzymes in the production of fine chemicals and therapeutic agents.

The treatment of common multi-factorial, system-wide diseases using multi-component therapeutics, such as herbal medicines, can be regarded as a “system to system” therapeutic approach. The pharmacokinetics (PK) of multi-component therapeutics is a great technical challenge, which has led to significant limitations in understanding the efficacies and toxicities of combination drugs and herbal medicines. Metabolomics has clearly demonstrated its value in elucidating the interaction of the biological system's genome with its environments, and recently been used in the PK analysis of drugs, xenobiotics and several nutrients. The metabolomics strategy can also be used in pharmacokinetic study of plant derived agents to demonstrate their biological fates, thereby linking the plant metabolome to human/ animal metabolome, and bridging the gap between multi-component agents and molecular pharmacology. This paper reviews the current progress of metabolomics based PK studies, presents the potentials and challenges of such a strategy for herbal medicines, as well as looks into the future of the role of metabolomics in the relationship between PK, PD and TOX of herbal medicines.

Increased understanding of the molecular mechanisms of tumor heterogeneity combined with rapid advances in the field of pharmacogenetics and pharmacogenomics have fuelled studies on individualizing anticancer therapy. Doxorubicin (Adriamycin), is an anthracycline glycoside antibiotic originally produced by Streptomyces peucetius var. caesius, and is widely used either as a single agent or in combination with other chemotherapeutic regimens for curative, adjuvant, and palliative treatment in cancer patients. The pharmacogenetics of doxorubicin has not been well characterized. The polygenic influence of functional candidate gene variants across doxorubicin biochemical pathway is hypothesized to contribute to its heterogeneity in disposition, influencing the efficacy of treatment and occurrence of adverse effects like cardiomyopathy in patients undergoing doxorubicin based adjuvant and neo-adjuvant chemotherapy. The pharmacogenetics of Asian population differs from that of other ethnic groups, particularly from Caucasian and African populations, and indicates an important role of ethnicity in determining predictive end points during chemotherapy and in individualizing treatment. This review comprehensively examines the pharmacogenetics of the regulatory nuclear receptor Pregnane-X Receptor (PXR), influx (SLC22A16) and efflux drug transporters (ABCB1, ABCG2, ABCC5, ABCB5 and RLIP76) and drug metabolizing enzymes (CBR1, CBR3) across the biochemical pathway of doxorubicin in Asian breast cancer patients receiving doxorubicin based adjuvant chemotherapy. The influence of functional genetic variants on the inter-individual variability in pharmacokinetics of doxorubicin and its major metabolite are also discussed. The incorporation of non-genetic factors and subsequent validation of these findings in different patient and population groups will be valuable in tailoring doxorubicin dosage regimens to an individual to maximize therapeutic efficacy and minimize adverse reactions, leading to improved clinical outcomes.