Expert Opinion on Drug Metabolism & Toxicology

doi: 10.1517/17425255.2012.686736pmid: N/A

Dong, Dong; Ako, Roland; Wu, Baojian

doi: 10.1517/17425255.2012.677027pmid: 22512672

Introduction: Cytosolic sulfotransferases (SULTs) are the enzymes that catalyze the sulfonation reaction, an important metabolic pathway for numerous endogenous and exogenous compounds. Human SULTs exhibit complex patterns of broad, differential and overlapping substrate selectivity. Moreover, these enzymes often display substrate inhibition kinetics (i.e., inhibition of the enzyme activity at high substrate concentrations). Areas covered: At present, the crystal structures for 12 human SULTs (i.e., SULT1A1, 1A2, 1A3, 1B1, 1C1, 1C2, 1C3, 1E1, 2A1, 2B1a, 2B1b and 4A1) are available, many of which are in complex with a substrate. This review describes the similarities and differences in these structures (particularly the active-site structures) of SULT enzymes. The authors also discuss the structural basis for understanding the catalytic mechanism, the substrate inhibition mechanisms, the cofactor (3'-phosphoadenosine 5'-phosphosulfate or PAPS) binding and the substrate recognition. Expert opinion: Correlations of the structural features (including conformational flexibility) in the active sites with the substrate profiles of several SULTs have been well established. One is encouraged to closely integrate in silico approaches with the structural knowledge of the active sites for development of a rationalized and accurate tool that is able to predict metabolism of SULTs toward chemicals and drug candidates.

Geldenhuys, Werner J; Allen, David D; Bloomquist, Jeffrey R

doi: 10.1517/17425255.2012.677433pmid: 22468700

Introduction: The blood–brain barrier (BBB) is a selectively permeable micro-vascular unit which prevents many central nervous system (CNS)-targeted compounds from reaching the brain. A significant problem in CNS drug development is the ability to model BBB permeability in a timely, reproducible and cost-effective manner. Through the years, several models have been used such as artificial membranes, cell culture and animal models. Areas covered: In this focused review, the authors cover novel models which have been developed or are in the process of being developed which can be used in modeling BBB. These models can either be used to determine BBB permeability or whether a compound may be disrupting the BBB. Many of these models lend themselves to high-throughput screening. The main model organisms covered here are the grasshopper (Locusta migratoria), fruit fly (Drosophila melanogaster) and zebrafish (Danio rerio). Expert opinion: Many of the models covered here have only recently been utilized for BBB studies and still needs to be fully studied for its impact on reducing costs during drug development. The strength of these models lay in the fact that a whole organism experiment can be done in high throughput fashion as compared with classical vertebrate models such as micro-dialysis.

Small, David M; Gobe, Glenda C

doi: 10.1517/17425255.2012.679657pmid: 22475359

Introduction: Acute kidney injury (AKI) in critically ill patients is closely associated with increased morbidity and mortality, yet there remains continued reliance on increased serum creatinine and blood urea nitrogen to diagnose AKI. These biomarkers increase only after significant renal structural damage has occurred. Recent research efforts have focused on discovery and validation of novel serum and urine biomarkers to detect AKI prior to extensive structural damage. Cytochrome c is best known as an indicator of cell death burden in any organ or tissue. It is released during mitochondrial damage that is associated with processing of apoptosis, cell lysis during necrosis and even reversible mitochondrial and cell injury. Areas covered: This article reviews the current literature on the potential for cytochrome c as an early biomarker of AKI. The article is based on PubMed searches, using the terms ‘acute kidney injury,’ ‘renal failure,’ ‘biomarker,’ ‘toxicity’ and ‘cytochrome c’, with a focus on experimental and clinical data. Expert opinion: Cytochrome c, as a biomarker, has the potential to improve outcome for AKI patients. Its release indicates mitochondrial damage, one of the earliest changes in cell injury and death. New mitochondrial-targeted therapeutics may be designed around this molecule. Its disadvantages include only transient increase at expression levels that are easily measurable and nonspecificity for kidney injury. The appropriate and optimal utilization of cytochrome c as a biomarker for AKI will be realized only after its complete characterization in experimental and clinical arenas.

Koczor, Christopher A; Torres, Rebecca A; Lewis, William

doi: 10.1517/17425255.2012.680885pmid: 22509856

Introduction: Two families of nucleoside analogs have been developed to treat viral infections and cancer, but these compounds can cause tissue- and cell-specific toxicity related to their uptake and subcellular activity, which are dictated by host enzymes and transporters. Cellular uptake of these compounds requires nucleoside transporters that share functional similarities but differ in substrate specificity. Tissue-specific cellular expression of these transporters enables nucleoside analogs to produce their tissue-specific toxic effects, a limiting factor in the treatment of retroviruses and cancer. Areas covered: This review discusses the families of nucleoside transporters and how they mediate cellular uptake of nucleoside analogs. Specific focus is placed on examples of known cases of transporter-mediated cellular toxicity and classification of the toxicities resulting. Efflux transporters are also explored as a contributor to analog toxicity and cell-specific effects. Expert opinion: Efforts to modulate transporter uptake/clearance remain long-term goals of oncologists and virologists. Accordingly, subcellular approaches that either increase or decrease intracellular nucleoside analog concentrations are eagerly sought and include transporter inhibitors and targeting transporter expression. However, additional understanding of nucleoside transporter kinetics, tissue expression and genetic polymorphisms is required to design better molecules and better therapies.

Yang, Chung S; Pan, Eva

doi: 10.1517/17425255.2012.681375pmid: 22509899

Introduction: Tea, made from the dried leaves of the plant Camellia sinensis Theaceae, is a very popular beverage consumed worldwide. Recently, green tea extract-based dietary supplements have also been widely consumed for the acclaimed beneficial health effects, such as weight reduction. Although tea consumption is considered to be innocuous, the potential interactions between tea polyphenols and drugs have been demonstrated in studies in vitro and in vivo. Areas covered: This article reviews the current literature on the chemistry and biotransformation of tea constituents, mainly catechins from green tea. The article also provides a review of their effects on the absorption, efflux, metabolism and elimination of different drugs. Expert opinion: Tea catechins may bind to certain drugs to affect their absorption and bioactivities. Tea catechins may inhibit the activities of drug-metabolizing enzymes and drug transporters or affect the expression of these proteins, either upregulation or downregulation. Although these effects have been demonstrated in studies in vitro and in animal models, such effects have only been observed in limited cases in humans at common doses of human tea consumption. The ingestion of tea catechins from dietary supplements, which could be in large bullet doses, may produce more profound effects on drug metabolism, and such effects with drugs need to be further investigated.

Rahimi, Roja; Abdollahi, Mohammad

doi: 10.1517/17425255.2012.680886pmid: 22606944

Introduction: Hypericum perforatum (HP), more commonly known as St. John's wort, is a popular medicinal herb used for the treatment of depression. HP affects the pharmacokinetics of many drugs by inducing cytochrome P450 (CYP) isozymes, such as CYP3A4, CYP2C19, CYP2C9, and the P-glycoprotein (P-gp) transporter. Areas covered: This review focuses on drugs that are metabolized by CYP3A4, CYP2C19, CYP2C9 and P-gp as their plasma concentrations show the effects of concomitant use of HP. For the purpose of this review, all electronic databases such as PubMed, Scopus, Google Scholar and Cochrane library were searched to identify in vitro, in vivo or human studies about the effects of HP on the metabolism of drugs. Data collected were published between 1966 and January 2012. Expert opinion: There are a number of drugs whose metabolism is reduced by HP. The authors point out that metabolic interactions between HP and drugs are not always unfavorable and sometimes have benefits (e.g., reduction of irinotecan toxicity and increase in clopidogrel responsiveness). HP does not have a significant influence on the kinetics of drugs such as carbamazepine, ibuprofen and theophylline. The use of HP preparations is not recommended in people who are taking immunosuppressants or cardiovascular drugs. With other medications, it is recommended that practitioners should only use HP preparations with a low hyperforin content and under careful monitoring. It is also recommended that because of the reduction in the bioavailability of oral contraceptives administered concurrently with HP, women who use HP preparations should use additional preventive methods to avoid unintended pregnancy.

Hutson, Janine R; Weitzman, Sheila; Schechter, Tal; Arceci, Robert J; Kim, Richard B; Finkelstein, Yaron

doi: 10.1517/17425255.2012.680884pmid: 22509821

Introduction: There is a lack of high-quality data regarding optimal chemotherapy dosage regimens among infants. Dosing regimens for chemotherapy during the first year of life are commonly based on empiric recommendations extrapolated from older children; however, balancing efficacy and toxicity is critical as severe adverse drug reactions may lead to treatment failure or reduced adherence to needed medications. Areas covered: This review describes pharmacokinetic and pharmacogenetic considerations when administering chemotherapeutic agents to infants. Examples of commonly used agents are provided with practical recommendations for dosing adjustments. Expert opinion: Optimal chemotherapy for children and infants in particular has lagged behind the remarkable progress in cancer treatment and it is clear that far more basic and clinical research are needed with respect to the mechanistic basis of age-dependent differences in pharmacokinetic parameters. More recent studies which have combined pharmacokinetic data with clinical toxicity and outcome data have resulted in a number of more evidence-based guidelines at least for the initial chemotherapy dosing; however, at present, the dosing of chemotherapy drugs in neonates and infants remains largely empiric.

Lai, Yurong; Varma, Manthena; Feng, Bo; Stephens, Joel Clay; Kimoto, Emi; El-Kattan, Ayman; Ichikawa, Katsuomi; Kikkawa, Hironori; Ono, Chiho; Suzuki, Akiyuki; Suzuki, Misaki; Yamamoto, Yuichi; Tremaine, Larry

Scheen, André J

doi: 10.1517/17425255.2012.686603pmid: 22587686

Introduction: Patients with type 2 diabetes (T2DM) are exposed to a high risk of cardiovascular disease (CVD) requiring a global therapeutic approach. Statin therapy has proven its efficacy in reducing CVD events in T2DM patients. Dipeptidylpeptidase-4 inhibitors (gliptins), which are increasingly used to target hyperglycemia, also offer promising preliminary results regarding a possible reduction in CVD events. As most patients with T2DM may be treated with both a statin and a gliptin, dual pharmacological therapy, possibly as a fixed-dose combination (FDC), deserves further consideration. Areas covered: The reader is provided with an update of information on the pharmacokinetics (PK) and pharmacodynamics (PD) of atorvastatin and sitagliptin. The article provides an analysis of the potential PK/PD interactions between the two compounds and puts into perspective the potential cardiovascular protection that such a dual therapy may offer in patients with T2DM. Expert opinion: Atorvastatin and sitagliptin are not prone to PK drug–drug interactions. Their coadministration, either separately or in an FDC, improves both blood glucose levels and cholesterol concentrations, without clinically relevant adverse events. The atorvastatin plus sitagliptin combination may be used to reduce LDL cholesterol and hyperglycemia in patients with T2DM, with the aim to improve CVD prognosis and adherence to therapy.