Current Drug Metabolism (v.17, #3)

Meet Our Editorial Board Member by Hiroshi Yamazaki (205-205).

Cannabinoids and Cytochrome P450 Interactions by Ond|ej Zendulka, Gabriela Dovrt|lová, Krist (206-226).
Objective: This review consists of three parts, representing three different possibilities of interactions between cannabinoid receptor ligands of both exogenous and endogenous origin and cytochrome P450 enzymes (CYPs). The first part deals with cannabinoids as CYP substrates, the second summarizes current knowledge on the influence of various cannabinoids on the metabolic activity of CYP, and the third outline a possible involvement of the endocannabinoid system and cannabinoid ligands in the regulation of CYP liver activity.
Methods: We performed a structured search of bibliographic and drug databases for peer-reviewed literature using focused review questions.
Results: Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic, in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19, and CYP3A4 catalyze most of their hydroxylations. Similarly, CYP represents a major metabolic pathway for both synthetic cannabinoids used therapeutically and drugs that are abused. In vitro experiments document the mostly CYP inhibitory activity of the major phytocannabinoids, with cannabidiol as the most potent inhibitor of many CYPs. The drug-drug interactions between cannabinoids and various drugs at the CYP level are reported, but their clinical relevance remains unclear. The direct activation/inhibition of nuclear receptors in the liver cells by cannabinoids may result in a change of CYP expression and activity. Finally, we hypothesize the interplay of central cannabinoid receptors with numerous nervous systems, resulting in a hormone-mediated signal towards nuclear receptors in hepatocytes.

Influence of CYP3A5 polymorphism on the pharmacokinetics of psychiatric drugs by Georgia Ragia, Marja-Liisa Dahl, Vangelis G. Manolopoulos (227-236).
Background: The contribution of the CYP3A5 enzyme to the metabolism of clinically used drugs has been established only for a few CYP3A substrates, such as the immunosuppressant tacrolimus, while for drugs used in the field of psychiatry its role is still vague. Methods: We herein discuss all published data on the contribution of CYP3A5 and its polymorphisms to the metabolism of antipsychotics and antidepressants that are known to be metabolized by CYP3A enzymes, as well as of carbamazepine, an antiepileptic drug used as mood stabilizer. Published papers from 1990 to April 2015 were retrieved from PubMed and Scopus by use of the keywords CYP3A5, CYP3A, gene polymorphism, antipsychotics, psychiatry, pharmacogenomics, haloperidol, risperidone, quetiapine, aripiprazole, clozapine, olanzapine, antidepressants, and carbamazepine. Results: Available evidence is only sparse and no firm conclusions can be drawn on whether CYP3A5 enzyme exhibits affinity and metabolic capacity similar to CYP3A4 for these drugs. Nevertheless, the role of CYP3A5 should be studied further, since there is evidence suggesting that CYP3A5 potentially catalyses alternative metabolic pathways that may give rise to intermediate metabolites with yet unknown pharmacologic properties and may also limit drug bioavailability through intestinal first pass metabolism. Additionally, expression of CYP3A5 may overcome CYP3A4 drug-drug interactions. Conclusions: Overall, CYP3A5 is an overlooked polymorphic enzyme and its potential in improving psychiatric pharmacogenomics remains to be explored. The impact of CYP3A5 pharmacogenetics in the clinical setting merits the attention of both researchers and clinicians.

Background: To date, the most effective way to treat HIV is to use a highly active antiretroviral therapy (HAART) that combines three or more different drugs. The usual regimen consists of two nucleoside reverse transcriptase inhibitors and either a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, or an integrase strand transfer inhibitor. Due to the emerging resistance against the nucleoside analogues in use, there is a continuous need for the development of such therapeutic molecules with different structural features.
Objectives: In this review, we would like to summarize the state of knowledge of the antiretroviral nucleoside analogues intracellular metabolism. Indeed, these molecules have to be phosphorylated in the cell, a process that is often a bottleneck, to produce their pharmacologically active triphosphorylated forms. These forms can be used by the HIV reverse transcriptase. Because they lack a 3'-hydroxyl group, they block further extension of the viral DNA, and finally lead to early chain termination. Several kinases can act on the phosphorylation of these drugs; most of them have low nucleoside/nucleotide specificity. On the other hand, there are also nucleotidases in the cell, which can reverse the phosphorylation process, thus shifting the equilibrium from the active triphosphorylated state to the non-active (not-, mono- or di-phosphorylated) states of these analogues.
Conclusion: Here, we would like to bring to the attention of the medicinal chemists that they have to take into account the limitation of the intracellular phosphorylation machinery when designing new nucleoside analogue drugs.

Optimizing DMPK Properties: Experiences from a Big Pharma DMPK Department by Anna-Karin Sohlenius-Sternbeck, Juliette Janson, Johan Bylund, Pawel Baranczewski, Anna Breitholtz-Emanuelsson, Yin Hu, Carrie Tsoi, Anders Lindgren, Olle Gissberg, Tjerk Bueters, Sveinn Briem, Sanja Juric, Jenny Johansson, Margareta Bergh, Janet Hoogstraate (253-270).
Background: The disposition of a drug is dependent on interactions between the body and the drug, its molecular properties and the physical and biological barriers presented in the body. In order for a drug to have a desired pharmacological effect it has to have the right properties to be able to reach the target site in sufficient concentration. This review details how drug metabolism and pharmacokinetics (DMPK) and physicochemical deliveries played an important role in data interpretation and compound optimization at AstraZeneca R&D in Södertälje, Sweden.
Methods: A selection of assays central in the evaluation of the DMPK properties of new chemical entities is presented, with guidance and consideration on assay outcome interpretation. Early in projects, solubility, LogD, permeability and metabolic stability were measured to support effective optimization of DMPK properties. Changes made to facilitate high throughput, efficient bioanalysis and the handling of large amounts of samples are described. Already early in drug discovery, we used an integrated approach for the prediction of the fate of drugs in human (early dose to man) based on data obtained from in vitro experiments. The early dose to man was refined with project progression, which triggered more intricate assays and experiments. At later stages, preclinical in vivo pharmacokinetic (PK) data was integrated with pharmacodynamics (PD) to allow predictions of required dose, dose intervals and exposure profile to achieve the desired effect in man.
Results and Conclusions: A well-defined work flow of DMPK activities from early lead identification up to the selection of a candidate drug was developed. This resulted in a cost effective and efficient optimization of chemical series, and facilitated informed decision making throughout project progress.

Variation of Pharmacokinetic Profiles of Some Antidiabetic Drugs from Nanostructured Formulations Administered Through Pulmonary Route by Biswajit Mukherjee, Paramita Paul, Ankan Choudhury, Sanchari Bhattacharya, Ruma Maji, Lopamudra Dutta (271-278).
Background: Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. WHO projects that diabetes death will be doubled between 2005 and 2030, where 347 million people worldwide had diabetes as per the report of 2013. The increase in the prevalence of diabetes is due to three influences - lifestyle, ethnicity, and age.
Methods: The present review summarizes the pharmacokinetic parameters and challenges in the field of nanoparticles and nanoliposomes of insulin and other antidiabetic drugs given through pulmonary route to treat diabetes effectively.
Results: Current challenges in diabetes management include optimizing the use of the already available therapies to ensure adequate glycemic condition, blood pressure, lipid control and to reduce complications. At present, several pieces of research have been focusing on new management options for diabetes. Among these options, the use of nanomedicine is becoming an eye catching and most promising one. Currently, nanoparticles and nanoliposomes are thrust areas of research to treat any deadly disease like diabetes. These drug delivery systems ultimately result in longer circulation half-lives, improved drug pharmacokinetics, and reduced side effects of therapeutically active substances that may be insulin and non-insulin.
Conclusions: Thus, the pulmonary route is the most promising alternative route of drug delivery since it is non-invasive and lungs have a large surface area, richly supplied by the capillary network, for absorption of drugs.

Recent Aspects of Osmotic Pump Systems: Functionalization, Clinical use and Advanced Imaging Technology by Jianting Chen, Hao Pan, Tiantian Ye, Dandan Liu, Qijun Li, Fen Chen, Xinggang Yang, Weisan Pan (279-291).
Background: Osmotic pump drug delivery systems are one of the most promising and widely developed systems. They are based on the principle of osmosis and are characterized by a zero-order release pattern independent of the physicochemical properties of the drug involved and some physiological factors. In the past 30 years, a series of difficulties, such as the very wide solubility range of different drugs, have been resolved accompanied by the development of various types of osmotic pumps. Furthermore, more advanced designs have been proposed according to practical requirements.
Methods: We started a systematic references collection on osmotic pump systems through different available databases. Then these information were analyzed and divided according to different subjects. Finally, we made clear our thought and begun to write it in a logical way.
Results: This review mainly concentrates on five kinds of functional osmotic pumps including technology combined, targeted, chronotherapy- based, ascending and compound osmotic pumps, involving ways to improve bioavailability and reduce side effects. Special attention is paid to the application of advanced imaging technologies to study osmotic pumps including the coating process, processing steps, polymer hydration and changes in the internal structure.
Conclusions: Present-day osmotic pumps not only produce a constant release, but also have the ability to produce adjustable release according to practical requirements. Hence, technology combined, targeted, chronotherapy-based, ascending and compound osmotic pumps are a positive development. These latest advances offer various advantages compared with the classic osmotic pump, and enable them to meet the new needs for clinical use with fewer side effects and improved safety. In addition, following the improvements in the versatility and complexity of the novel osmotic pump system, conventional assessing parameters may fail to meet the increasing demand for information. Hence, novel imaging and monitoring technologies have been employed to monitor osmotic pumps from the coating process, processing steps, and polymer hydration to the changes in polymeric internal structure, which are associated with the different performance offered by the in vivo action of similar products.

Occurrence, Human Intake and Biodegradation of Estrogen-Like Nonylphenols and Octylphenols by Shir-Ly Huang, Nguyen Ngoc Tuan, Kyoung Lee (293-302).
Background: Long-chain alkylphenols, such as nonylphenols and octylphenols, are man-made compounds with estrogen-like activity and considered to be endocrine disputing chemicals. They are known to influence sexual development and reproduction of humans and other animals, therefore cause health and ecological concerns.
Objective: This review aims to identify the key findings presented in recent scientific literature with respect to the presence of long-chain alkylphenols in food, intake by different populations and describe the metabolism by human and the mechanisms to disrupt the estrogenic activity of nonylphenols and octylphenols by bacteria and fungi in the environment.
Method: The current knowledge related to the physicochemical properties, source, occurrence, toxic effects, level in foods, human intake, elimination and metabolism of long-chain alkylphenols was summarized.
Results: Long-chain alkylphenols have been detected in soil, surface and ground water, sediments, wastewater effluent, air and in most foods. The daily human intake of 4-nonylphenols and 4-octylphenols has been compared among different population. A comprehensive summary of the major degradation pathways and mechanism in bacteria, fungi, yeasts and vertebrates was described.
Conclusion: The findings of this review revealed the wide distribution of long-chain alkylphenols in various environments and contamination in foods. Therefore, further investigation of long-term exposure is necessary to comprehensively evaluate the potential health risks to humans. The diverse biodegradation mechanisms can be used in the removal of these compounds before entering food chains. The review provides indication as to how it might be possible to reduce the adverse effects on human health from estrogen-like long-chain alkylphenols.

Smad7 and its Potential as Therapeutic Target in Inflammatory Bowel Diseases by Federica Laudisi, Vincenzo Dinallo, Davide Di Fusco, Giovanni Monteleone (303-306).
Background: The etiology of Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD) in humans, is still unknown, but evidence suggests that genetic and environmental factors interact to promote an excessive immune response that leads to tissue damage. Defects in the counter-regulatory mechanisms are also supposed to make a major contribution to the amplification and maintenance of the IBD-related inflammatory response. One such a mechanism involves TGF-β;1, a cytokine synthesized by both immune and non-immune cells in the gut, which is essential in the maintenance of immune homeostasis. In both CD and UC, active inflammation occurs in areas characterized by enhanced production of TGF-β;1 and reduced ability of this cytokine to activate Smad-associated signaling and suppress inflammatory pathways. The defective TGF-β;1 activity is due to elevated levels of Smad7, an intracellular protein that inhibits TGF-β;1-associated Smad signaling.
Methods: Data from original studies and reviews were selected through an accurate research of the literature using the terms “IBD”, “colitis”, “Crohn's disease”, “Smad7”, “TGF-β;1”, “antisense oligonucleotide” and “Mongersen”.
Results: Twenty-fours studies describing the most accredited hypothesis about IBD pathogenesis and the role of Smad7 in the negative control of TGF-β;1 were discussed in the review. Additionally, we reported data from original work illustrating the generation and the in vitro and in vivo effect of a specific Smad7 antisense oligonucleotide on intestinal inflammatory signals. We also discussed the results of phase 1 and phase 2 studies assessing the safety profile and clinical efficacy of Mongersen, an oral Smad7 antisense oligonucleotidecontaining drug, in patients with active CD.
Conclusions: Data indicate that, in IBD, high Smad7 contributes to sustain detrimental immune responses and knockdown of this molecule can help attenuate the ongoing mucosal inflammation in patients with such disorders.