Lipophilic conjugates (LCs) of small molecule drugs have been used widely in clinical and pre-clinical studies to achieve a number of pharmacokinetic and therapeutic benefits. For example, lipophilic derivatives of drugs are employed in several long acting injectable products to provide sustained drug exposure for hormone replacement therapy and to treat conditions such as neuropsychiatric diseases. LCs can also be used to modulate drug metabolism, and to enhance drug permeation across membranes, either by increasing lipophilicity to enhance passive diffusion or by increasing protein-mediated active transport. Furthermore, such conjugation strategies have been employed to promote drug association with endogenous macromolecular carriers (e.g. albumin and lipoproteins), and this in turn results in altered drug distribution and pharmacokinetic profiles, where the changes can be 'general' (e.g. prolonged plasma half-life) or 'specific' (e.g. enhanced delivery to specific tissues in parallel with the macromolecular carriers). Another utility of LCs is to enhance the encapsulation of drugs within engineered nanoscale drug delivery systems, in order to best take advantage of the targeting and pharmacokinetic benefits of nanomedicines. The current review provides a summary of the mechanisms by which lipophilic conjugates, including in combination with delivery vehicles, can be used to control drug delivery, distribution and therapeutic profiles. The article is structured into sections which highlight a specific benefit of LCs and then demonstrate this benefit with case studies. The review attempts to provide a toolbox to assist researchers to design and optimise drug candidates, including consideration of drug-formulation compatibility.

Lipophilic Conjugates of Drugs: A Tool to Improve Drug Pharmacokinetic and Therapeutic Profiles.

Androgens are an important and diverse group of steroid hormone molecular species. They play varied functional roles, such as the control of metabolic energy fate and partition, the maintenance of skeletal and body protein and integrity and the development of brain capabilities and behavioral setup (including those factors defining maleness). In addition, androgens are the precursors of estrogens, with which they share an extensive control of the reproductive mechanisms (in both sexes). In this review, the types of androgens, their functions and signaling are tabulated and described, including some less-known functions. The close interrelationship between corticosteroids and androgens is also analyzed, centered in the adrenal cortex, together with the main feedback control systems of the hypothalamic–hypophysis–gonads axis, and its modulation by the metabolic environment, sex, age and health. Testosterone (T) is singled out because of its high synthesis rate and turnover, but also because age-related hypogonadism is a key signal for the biologically planned early obsolescence of men, and the delayed onset of a faster rate of functional losses in women after menopause. The close collaboration of T with estradiol (E2) active in the maintenance of body metabolic systems is also presented Their parallel insufficiency has been directly related to the ravages of senescence and the metabolic syndrome constellation of disorders. The clinical use of T to correct hypoandrogenism helps maintain the functionality of core metabolism, limiting excess fat deposition, sarcopenia and cognoscitive frailty (part of these effects are due to the E2 generated from T). The effectiveness of using lipophilic T esters for T replacement treatments is analyzed in depth, and the main problems derived from their application are discussed.

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The Roles of Androgens in Humans: Biology, Metabolic Regulation and Health

Male hypogonadism is often treated by testosterone (T) replacement therapy such as oral administration of the ester prodrug, testosterone undecanoate (TU). However, the systemic exposure to T following oral TU is very low due to esterase-mediated metabolism, particularly in the small intestine. The aim of this work was to examine the esterase-inhibitory effect of natural fruit extract of strawberry (STW) on the intestinal degradation of TU as a potential approach to increasing the oral bioavailability of T. Herein, the hydrolysis of TU was assessed in fasted state simulated intestinal fluid with added esterase activity (FaSSIF/ES) and Caco-2 cell homogenates in the presence of STW extract. It is noteworthy that STW substantially inhibited the degradation of TU in FaSSIF/ES and Caco-2 cell homogenates at concentrations that could be achieved following oral consumption of less than one serving of STW fruit. This can significantly increase the fraction of unhydrolyzed TU in the intestinal lumen as well as in enterocytes. In addition, it was demonstrated that TU has high intestinal lymphatic transport potential as the association of TU with plasma-derived human chylomicrons was in the range of 84%. Therefore, oral co-administration of TU with STW could potentially increase the intestinal stability of TU and consequently the contribution of lymphatically delivered TU to the systemic exposure of T in vivo.

Strawberry Decreases Intraluminal and Intestinal Wall Hydrolysis of Testosterone Undecanoate.

Routine therapeutic drug monitoring (TDM) relies heavily on measuring trough drug concentrations. Trough concentrations are affected not only by drug bioavailability and clearance, but also by various patient and disease factors and the volume of distribution. This often makes interpreting differences in drug exposure from trough data challenging. This study aimed to combine the advantages of top-down analysis of therapeutic drug monitoring data with bottom-up physiologically-based pharmacokinetic (PBPK) modeling to investigate the effect of declining renal function in chronic kidney disease (CKD) on the nonrenal intrinsic metabolic clearance (CLint) of tacrolimus as a case example.Data on biochemistry, demographics, and kidney function, along with 1167 tacrolimus trough concentrations for 40 renal transplant patients, were collected from the Salford Royal Hospital's database. A reduced PBPK model was developed to estimate CLint for each patient. Personalized unbound fractions, blood-to-plasma ratios, and drug affinities for various tissues were used as priors to estimate the apparent volume of distribution. Kidney function based on the estimated glomerular filtration rate (eGFR) was assessed as a covariate for CLint using the stochastic approximation of expectation and maximization method.At baseline, the median (interquartile range) eGFR was 45 (34.5-55.5) mL/min/1.73 m2. A significant but weak correlation was observed between tacrolimus CLint and eGFR (r = 0.2, P < 0.001). The CLint declined gradually (up to 36%) with CKD progression. Tacrolimus CLint did not differ significantly between stable and failing transplant patients.Kidney function deterioration in CKD can affect nonrenal CLint for drugs that undergo extensive hepatic metabolism, such as tacrolimus, with critical implications in clinical practice. This study demonstrates the advantages of combining prior system information (via PBPK) to investigate covariate effects in sparse real-world datasets. 

Using Prior Knowledge on Systems Through PBPK to Gain Further Insight into Routine Clinical Data on Trough Concentrations: The Case of Tacrolimus in Chronic Kidney Disease

Green chemistry and anti-inflammatory activity of silver nanoparticles using aqueous curcumin extract

The bioavailability of orally administered drugs could be impacted by intestinal and hepatic first-pass metabolism. Testosterone undecanoate (TU), an orally administered ester prodrug of testosterone, is significantly subjected to first-pass metabolism. However, the individual contribution of intestinal and hepatic first-pass metabolism is not well determined. Therefore, the aim of the current study was to predict the metabolic contribution of each site. The hydrolysis–time profiles of TU incubation in human liver microsomes and Caco-2 cell homogenate were used to predict hepatic and intestinal first-pass metabolism, respectively. The in vitro half-life (t1/2 inv) for the hydrolysis of TU in microsomal mixtures was 28.31 ± 3.51 min. By applying the “well-stirred” model, the fraction of TU that could escape hepatic first-pass metabolism (FH) was predicted as 0.915 ± 0.009. The incubation of TU in Caco-2 cell homogenate yielded t1/2 inv of 109.28 ± 21.42 min, which was applied in a “Q gut” model to estimate the fraction of TU that would escape intestinal first-pass metabolism (FG) as 0.114 ± 0.02. Accordingly, only 11% of the absorbed fraction of TU could escape intestinal metabolism, while 91% can pass through hepatic metabolism. Hence, compared to the liver, the intestinal wall is the main site where TU is significantly metabolised during first-pass effect.

Predicting Intestinal and Hepatic First-Pass Metabolism of Orally Administered Testosterone Undecanoate

Poor control of blood glucose levels remains a serious challenge for diabetic patients. Silver nanoparticles were employed as antidiabetic agents due to their unique biological capabilities in growing insulin levels in diabetic animal models. In this study, a cost-effective and eco-friendly process for the production of silver nanorods (AgNRs) is described, and berberine extract has been successfully employed as a capping and reduction agent using an innovative method of green chemistry. UV–vis spectroscopy, field emission scanning electron microscopy (FESEM), and X-ray diffraction (XRD) studies were employed to characterize AgNRs. The objective of the current research was to treat or avoid hyperglycemia in rats caused by streptozotocin. Therefore, 25 male albino rats were split into five categories: Healthy control rats; diabetic rats untreated; diabetic rats treated with Glimepiride as a standard drug; diabetic rats treated with AgNRs; rats treated with AgNRs before being streptozotocin-induced diabetes. The diabetic group getting AgNRs exhibited significantly lower fasting blood glucose (FBG) readings than the diabetic control group (p < 0.001). The effects of AgNRs were also tested on serum lipid profile levels, which serve as an important biomarker in diabetes. Significantly, Ag NRs were found to improve lipid metabolism in the diabetic rats' group (p < 0.001). Additionally, pre-treatment with AgNRs was found to maintain normal blood glucose and lipid profile levels in rats receiving streptozotocin (p < 0.001). Together, these findings show a novel potential protective and anti-diabetic impact, which may be applied in designing novel future therapies for treating DM. 

Green biosynthesis of berberine-mediated silver nanorods: Their protective and antidiabetic effects in streptozotocin-induced diabetic rats

New nanocomposite based on chitosan and acrylamide and silver nanoparticles has been prepared to produce wound dressing has superior properties as heamostatic and antibacterial activity. Chitosan successfully grafted with acrylamide via free radical copolymerization using potassium persulphate. Four different chitosan grafted acrylamide prepared and fully characterized through nitrogen content and ATR/IR. Cs-g- PAAM partially hydrolyzed at basic condition in presence of silver nitrate in order to prepare Cs-g-PAAm-co-PAAc/Ag nanocomposite. The optimum condition for preparing homogenous and well distributed was examined using grafted polymers were characterized using TEM and UV-vis absorption. Cs:PAAm (1:1) showed homogenous spherical silver nanoparticles and distributed particles lying at nano size range between 10-30 nm.

https://ejchem.journals.ekb.eg/article_170163_b6bfb9a2f04700fbeacaa553c3df0bac.pdf

Yousaf Dawood

Papers

Predicting Intestinal and Hepatic First-Pass Metabolism of Orally Administered Testosterone Undecanoate

Green biosynthesis of berberine-mediated silver nanorods: Their protective and antidiabetic effects in streptozotocin-induced diabetic rats

Strawberry Decreases Intraluminal and Intestinal Wall Hydrolysis of Testosterone Undecanoate.

Green chemistry and anti-inflammatory activity of silver nanoparticles using aqueous curcumin extract

Synthesis of Chitosan –g-Acrylamide-Co-Acrylic Acid /Ag Nanocomposite For Extended Wound Healing Application