The absorption and distribution of radiocarbon-labeled urea at the ultratrace level were investigated with a 14C-AMS biotracer method. The radiopharmaceutical concentrations in the plasma, heart, liver, spleen, lung, kidney, stomach, brain, bladder, muscle, testis, and fat of rats after oral administration of 14C urea at ultratrace doses were determined by AMS, and the concentration-time curves in plasma and tissues and pharmacokinetic distribution data were obtained. This study provides an analytical method for the pharmacokinetic parameters and tissue distribution of exogenous urea in rats at ultratrace doses and explores the feasibility of evaluation and long-term tracking of ultratrace doses of drugs with AMS.

The ongoing pandemic, COVID-19 (SARS-CoV-2), has afflicted millions of people around the world, necessitating that the scientific community work, diligently and promptly, on suitable medicaments. Although vaccination programs have been run globally, the new variants of COVID-19 make it difficult to restrict the spread of the virus by vaccination alone. The combination of vaccination with anti-viral drug formulation is an ideal strategy for tackling the current pandemic situation. Drugs approved by the United States Food and Drug Administration (FDA), such as Remdesivir, have been found to be of little or no benefit. On the other hand, re-purposing of FDA-approved drugs, such as niclosamide (NIC), has offered promise but its applicability is limited due to its poor aqueous solubility and, therefore, low bioavailability. With advanced nano-pharmaceutical approaches, re-purposing this drug in a suitable drug-carrier for a better outcome may be possible. In the current study, an attempt was made to explore the loading of NIC into exfoliated layered double hydroxide nanoparticles (X-LDH NPs); prepared NIC-X-LDH NPs were further modified with eudragit S100 (ES100), an enteric coating polymer, to make the final product, ES100-NIC-X-LDH NPs, to improve absorption by the gastro/intestinal tract (GIT). Furthermore, Tween 60 was added as a coating on ES100-NIC-X-LDH NPs, not just to enhance its in vitro and in vivo stability, but also to enhance its mucoadhesive property, and to obtain, ultimately, better in vivo pharmacokinetic (PK) parameters upon oral administration. Release of NIC from Tween 60-ES100-NIC-X-LDH NPs was found to be greater under gastro/intestinal solution within a shorter period of time than the uncoated samples. The in vivo analysis revealed that Tween 60-ES100-NIC-X-LDH NPs were able to maintain a therapeutically relevant NIC plasma concentration in terms of PK parameters compared to the commercially available Yomesan®, proving that the new formulation might prove to be an effective oral drug-delivery system to deal with the SARS-CoV-2 viral infections. Further studies are required to ensure their safety and anti-viral efficacy.

Precision medicine is an approach to maximise the effectiveness of disease treatment and prevention and minimise harm from medications by considering relevant demographic, clinical, genomic and environmental factors in making treatment decisions. Precision medicine is complex, even for decisions about single drugs for single diseases, as it requires expert consideration of multiple measurable factors that affect pharmacokinetics and pharmacodynamics, and many patient-specific variables. Given the increasing number of patients with multiple conditions and medications, there is a need to apply lessons learned from precision medicine in monotherapy and single disease management to optimise polypharmacy. However, precision medicine for optimisation of polypharmacy is particularly challenging because of the vast number of interacting factors that influence drug use and response. In this narrative review, we aim to provide and apply the latest research findings to achieve precision medicine in the context of polypharmacy. Specifically, this review aims to (1) summarise challenges in achieving precision medicine specific to polypharmacy; (2) synthesise the current approaches to precision medicine in polypharmacy; (3) provide a summary of the literature in the field of prediction of unknown drug–drug interactions (DDI) and (4) propose a novel approach to provide precision medicine for patients with polypharmacy. For our proposed model to be implemented in routine clinical practice, a comprehensive intervention bundle needs to be integrated into the electronic medical record using bioinformatic approaches on a wide range of data to predict the effects of polypharmacy regimens on an individual. In addition, clinicians need to be trained to interpret the results of data from sources including pharmacogenomic testing, DDI prediction and physiological-pharmacokinetic-pharmacodynamic modelling to inform their medication reviews. Future studies are needed to evaluate the efficacy of this model and to test generalisability so that it can be implemented at scale, aiming to improve outcomes in people with polypharmacy.

Understanding the transfer of polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) as well as polychlorinated biphenyls (PCBs) from oral exposure into cow’s milk is not purely an experimental endeavour, as it has produced a large corpus of theoretical work. This work consists of a variety of predictive toxicokinetic models in the realms of health and environmental risk assessment and risk management. Their purpose is to provide mathematical predictive tools to organise and integrate knowledge on the absorption, distribution, metabolism and excretion processes. Toxicokinetic models are based on more than 50 years of transfer studies summarised in part I of this review series. Here in part II, several of these models are described and systematically classified with a focus on their applicability to risk analysis as well as their limitations. This part of the review highlights the opportunities and challenges along the way towards accurate, congener-specific predictive models applicable to changing animal breeds and husbandry conditions.

Fisetin, a polyphenol found in several fruits and vegetables, has shown potential health benefits in many pre-clinical studies for neuroprotection, cardioprotection, chemoprevention, diabetes, inflammation and oxidative stress. However, the clinical effectiveness of fisetin may be limited by its poor bioavailability when ingested. Using a novel green technology of Hybrid-FENUMAT™, a food-grade fisetin formulation (FF-20) was developed through encapsulation of fisetin micelles into fenugreek galactomannan (FG) hydrogel scaffold to improve its physical characteristics and bioavailability. This is the first human pharmacokinetic study of fisetin following a single-dose, comparative, double-blinded, cross-over protocol, supplementing with FF-20 and unformulated fisetin (UF). Fifteen healthy volunteers were given a single dose of 1000 mg UF or 1000 mg FF-20 (delivering 192 mg fisetin) with a 10-d washout period between each dose. Blood samples were taken at 0⋅5, 1, 2, 3, 5, 8 and 12 h after both days of supplementation to quantify fisetin and geraldol, an active metabolite. The plasma concentration of fisetin when individuals consumed FF-20 was 26⋅9-fold greater than UF as determined by the area under the curve over 12 h [AUC0–12 h (FF-20) = 341⋅4 v. AUC0–12 h (UF) = 12⋅67]. The maximum plasma concentration (Cmax) was also more than twenty-three times higher when supplemented with FF-20 (238⋅2 ng/ml) compared to UF (9⋅97 ng/ml). The encapsulation also reduced the amount of conversion of fisetin to geraldol. No adverse events were reported during the study. Therefore, the encapsulation of fisetin into FG dietary fibre hydrogel scaffold could improve its delivery and bioavailability in human subjects.

Multi-compartment models described by systems of linear ordinary differential equations are considered. Catenary models are a particular class where the compartments are arranged in a chain. A unified methodology based on the Laplace transform is utilised to solve direct and inverse problems for multi-compartment models. Explicit formulas for the parameters in a catenary model are obtained in terms of the roots of elementary symmetric polynomials. A method to estimate parameters for a general multi-compartment model is also provided. Results of numerical simulations are presented to illustrate the effectiveness of the approach.

Coenzyme Q10 (CoQ10), a lipid involved in ATP synthesis, exhibits very limited oral absorption, and its endogenous production decreases with ageing and with the occurrence of oxidative stress. Our group previously showed that monoglycerides omega-3 (MAG-OM3) increase OM3 plasma concentrations. Since CoQ10 is liposoluble, we hypothesised that its 48 h pharmacokinetics is higher when provided with MAG-OM3 compared to CoQ10 alone (in powder form) or added to rice oil (a neutral triacylglycerol oil). A randomised triple-blind crossover study was performed with fifteen men and fifteen women consuming the three supplements providing 200 mg of CoQ10 in a random order. Blood samples were collected before (t = 0) and 1, 3, 5, 6, 7, 8, 10, 11, 24 and 48 h after the supplement intake. Plasma total CoQ10 concentrations were analysed on ultrahigh-performance liquid chromatography coupled to a tandem mass spectrometer (UPLC-MS/MS). Participants were 26⋅1 ± 4⋅8 years old. When CoQ10 was provided with rice or MAG-OM3 oils, the 48 h area under the curve (AUC 0–48 h) was approximately two times higher compared to when provided without an oil. The delta max concentration (ΔCmax) of plasma CoQ10 was, respectively, 2 (MAG-OM3) and 2⋅5 (rice oil) times higher compared to CoQ10 alone. There was a significant sex by treatment interaction (P = 0⋅0250) for the AUC 0–6 h supporting that in postprandial, men and women do not respond the same way to the different supplement. Women had a higher CoQ10 concentration 48 h after the single-dose intake compared to men. We conclude that CoQ10 supplements must be provided with lipids, and their kinetics is different between men and women.

There are significant differences between men and women in the efficacy and tolerability of antipsychotic drugs. Here, we provide a comprehensive overview of what is currently known about the pharmacokinetics and pharmacodynamics of antipsychotics in women with schizophrenia spectrum disorders (SSDs) and translate these insights into considerations for clinical practice. Slower drug absorption, metabolism and excretion in women all lead to higher plasma levels, which increase the risk for side-effects. Moreover, women reach higher dopamine receptor occupancy compared to men at similar serum levels, since oestrogens increase dopamine sensitivity. As current treatment guidelines are based on studies predominantly conducted in men, women are likely to be overmedicated by default. The risk of overmedicating generally increases when sex hormone levels are high (e.g. during ovulation and gestation), whereas higher doses may be required during low-hormonal phases (e.g. during menstruation and menopause). For premenopausal women, with the exceptions of quetiapine and lurasidone, doses of antipsychotics should be lower with largest adjustments required for olanzapine. Clinicians should be wary of side-effects that are particularly harmful in women, such as hyperprolactinaemia which can cause oestrogen deficiency and metabolic symptoms that may cause cardiovascular diseases. Given the protective effects of oestrogens on the course of SSD, oestrogen replacement therapy should be considered for postmenopausal patients, who are more vulnerable to side-effects and yet require higher dosages of most antipsychotics to reach similar efficacy. In conclusion, there is a need for tailored, female-specific prescription guidelines, which take into account adjustments required across different phases of life.

Smoking is highly prevalent in the psychiatric population, and hospital admittance usually results in partial or complete smoking cessation. Tobacco use is known to affect the metabolism of certain psychoactive drugs, but whether smoking influences the plasma concentration of tricyclic antidepressants (TCAs) remains unclear. This article investigates the possible effect of smoking on the plasma concentration of TCAs. A systematic review of the literature available on PubMed and EMBASE as of October 2020 was carried out using PRISMA guidelines. Studies reporting plasma concentrations of any TCA in both a smoking and a non-smoking group were included and compared. Ten eligible studies were identified and included. In the eight studies investigating the effect of smoking on amitriptyline and/or nortriptyline, five studies found no significant effect. Two studies investigating the effect of smoking on imipramine found a significant effect, and one study investigating the effect of smoking on doxepin found no significant effect. The majority of studies included in this review were influenced by small study populations and other methodical issues. The effect of smoking on the plasma concentration of TCAs is still not entirely clear. There is a possibility that smoking affects the distribution of TCA metabolites, but this is probably not of clinical importance.