Current Drug Metabolism - Volume 15, Issue 10, 2014

In recent years, the functional interplay between drug-metabolizing enzymes (DMEs) and drug transporters (DTs) in drug absorption and disposition, as well as the complex drug interactions (DIs), has become an intriguing contention, which has also been termed the “transport–metabolism interplay”. The current mechanistic understanding for this interplay is first discussed. In the present article, studies investigating the interplay between cytochrome P450 enzymes (CYPs) and efflux transporters have been systematically reviewed in vitro, in situ, in silico, in animals and humans, followed by CYPs–uptake transporters, CYPs–uptake transporters-efflux transporters, and phase II metabolic enzymes–transporters interplay studies. Although several cellular, isolated organ and whole animal studies, in conjunction with simulation and modelling, have addressed the issue that DMEs and DTs can work cooperatively to affect the bioavailability of shared substrate drugs, convincing evidences in human studies are still lacking. Furthermore, the functional interplay between DMEs and DTs will be highly substrate- and dose- dependent. Additionally, we review recent studies to evaluate the influence of genetic variations in the interplay between DMEs and DTs, which might be helpful for the prediction of pharmacokinetics (PK) and possible DIs in human more correctly. There is strong evidence of coordinately regulated DEMs and DTs gene expression and protein activity (e.g. nuclear receptors). Taken together, further investigations and analysis are urgently needed to explore the functional interplay of DMEs and DTs and to delineate the underlying mechanisms.

The safety and efficacy of herbal medicines remain major issues of concern especially in the developing world where the use is high. The World Health Organisation estimates up to 80% of the population in Africa relies on herbal medicines for treatment of many diseases. Minimum safety evaluations need to be done for both the herbal and conventional drugs, in particular when there is a high likelihood of co-administration. This is particularly important in Africa where there is increased access to antiretrovirals in the treatment of HIV/AIDS, which are being used in a population background characterized by rampant use of herbal medicines. Many techniques used in the discovery and evaluation of conventional drugs can be adapted to herbal medicines. Such evaluations will add value to herbal medicines as doctors and patients will be better informed on which drugs and herbal medicines to take or not take together. This can also lead to the adoption of guidelines by regulatory agents such as the European Medicines Agency (EMA), Food and Drug Administration (FDA) and governmental agencies controlling the use of medicines. Of current interest is the evaluation of drug-herb interactions (DHI) involving the absorption, distribution, metabolism and excretion (ADME) of medicines where there is a promising possibility to adopt the current FDA and EMA guidelines on the evaluation of herbal medicines for drug-drug interactions (DDI). In this review we demonstrate progress made so far in DHI and point to possible future developments that will contribute to the safe use of herbal medicines.

Sucroferric oxyhydroxide (VELPHORO®) is a polynuclear iron-based phosphate binder recently approved for the treatment of hyperphosphataemia in patients with chronic kidney disease (CKD). As a number of the available phosphate binders do not provide the optimal combination of good efficacy, adequate tolerability and low pill burden, sucroferric oxyhydroxide constitutes a promising alternative. Among the attributes of an ideal phosphate binder is minimal absorption and, hence, low risk of systemic toxicity. Accordingly, the iron-releasing properties and absorption, distribution, metabolism and excretion (ADME) profile of sucroferric oxyhydroxide, as well as the possibility of iron accumulation and toxicity, were investigated in a series of preclinical studies. The effect of sucroferric oxyhydroxide on the progression of vascular calcification was also investigated. Sucroferric oxyhydroxide exhibited a high phosphate-binding capacity and low iron-releasing properties across the physiological pH range found in the gastrointestinal tract. In the ADME studies, uptake of 59Fe-radiolabelled sucroferric oxyhydroxide was low in rats and dogs (<1% from a 50 mg Fe/kg bodyweight dose), with the majority of absorbed iron located in red blood cells. Long-term (up to 2 years) administration of sucroferric oxyhydroxide in rats and dogs was associated with modest increases in tissue iron levels and no iron toxicity. Moreoever, in uraemic rats, sucroferric oxyhydroxide was associated with reduced progression of vascular calcification compared with calcium carbonate. In conclusion, sucroferric oxyhydroxide offers a new option for the treatment of hyperphosphataemia, with a high phosphate-binding capacity, minimal iron release, and low potential for iron accumulation and toxicity.

The research of drug metabolism is essential for successful drug discovery. Phytochemicals, particularly those from herbal medicines, have the potential to affect diseases such as cancer, heart disease, diabetes, and high blood pressure, etc., showing great advantages in disease prevention and personalized treatment. In the past decade, phytochemical metabolism played a major role in the discovery of valuable leading compounds of new drugs. However, the metabolic studies of phytochemical compounds are extremely challenging due to numerous analogs with similar structures, complex endogenous matrices with multi-components in biofluids and cell or tissue extracts. For the feasibility of monitoring phytochemical metabolism, suitable bioanalytical tools and strategies have to be developed and validated. Here we critically review the literature from 2009 to 2014, and present generalized strategy for phytochemical metabolism in biological matrices, including the methodology of metabolism, sample preparation methods and detection techniques. In addition, the present paper covers the diverse aspects of metabolism studies on phenolic acids, flavonoids, anthraquinones, alkaloids, terpenoids, coumarins, lignans and steroids in medicinal plants. Finally, prospects for further research are also considered.