All disease begins in the gut: Influence of gastrointestinal disorders and surgery on oral drug performance

The term "disease" conjures up a plethora of graphic imagery for many, and the use of drugs to combat symptoms and treat underlying pathology is at the core of modern medicine. However, the effects of the various gastrointestinal diseases, infections, co-morbidities and the impact of gastrointestinal surgery on the pharmacokinetic behaviour of drugs have been largely overlooked. The better elucidation of disease pathology and the role of underlying cellular and molecular mechanisms have increased our knowledge as far as diagnoses and prognoses are concerned. In addition, the recent advances in our understanding of the intestinal microbiome have linked the composition and function of gut microbiota to disease predisposition and development. However, this knowledge applies less so in the context of drug absorption and distribution mechanisms for orally administered dosage forms. Here, we revisit and re-evaluate the influence of a portfolio of gastrointestinal diseases and surgical effects on the functionality of the gastrointestinal tract, their implications for drug delivery and attempt to uncover significant links for clinical practice

P-glycoprotein expression in the gastrointestinal tract of male and female rats is influenced differently by food

The aim of this study was to explore the influence of food on P-glycoprotein (P-gp) relative expression in both male and female rats, and its effect on intestinal permeation of P-gp substrates (ranitidine and ganciclovir) and a P-gp non-substrate (metformin). The intestine of 12 male and 12 female Wistar rats were excised and segmented into the duodenum, jejunum, ileum and colon. P-gp extracted from each segment was then determined via Western-blotting. In male rats, the relative P-gp expression decreased significantly after food intake in all segments of the intestine except in the duodenum. The most notable change was demonstrated in the colon where relative expression decreased from 1.75 ± 0.36 in the fasted-state to 0.31 ± 0.15 in the fed-state. In female rats, a fundamentally different result was observed. Food ingestion resulted in a significant increase in relative P-gp expression in all regions of the intestine except in the colon. The largest difference was observed in the jejunum of the fed-state female rat intestine where P-gp expression was 1.76 ± 0.95 which was a six-fold increase from the fasted state at 0.34 ± 0.13. Intestinal permeation studies in an Ussing chamber showed that both ganciclovir and ranitidine exhibited a sex difference in intestinal permeability in the fasted-state. No sex differences and food effects were observed on metformin small intestine permeability. The permeability results of the three drugs highly supported that there was a sex-related food effect on P-gp function in the small intestine. In summary, the current study reports stark differences between male and female rats at a physiological level relating to P-gp expression and the influence of food

Let's talk about sex: Differences in drug therapy in males and females

Professor Henry Higgins in My Fair Lady said, ‘Why can’t a woman be more like a man?’. Perhaps unintended, such narration extends to the reality of current drug development. A clear sex-gap exists in pharmaceutical research spanning from preclinical studies, clinical trials to post-marketing surveillance with a bias towards males. Consequently, women experience adverse drug reactions from approved drug products more often than men. Distinct differences in pharmaceutical response across drug classes and the lack of understanding of disease pathophysiology also exists between the sexes, often leading to suboptimal drug therapy in women. This review explores the influence of sex as a biological variable in drug delivery, pharmacokinetic response and overall efficacy in the context of pharmaceutical research and practice in the clinic. Prospective recommendations are provided to guide researchers towards the consideration of sex differences in methodologies and analyses. The promotion of disaggregating data according to sex to strengthen scientific rigour, encouraging innovation through the personalisation of medicines and adopting machine learning algorithms is vital for optimised drug development in the sexes and population health equity

Gut reaction: impact of systemic diseases on gastrointestinal physiology and drug absorption

It was in 400 BC that Hippocrates reportedly stated that "death sits in the colon". The growth in our knowledge of the intestinal microbiome and the gut-brain axis, their function and imbalance, has distinctly uncovered the complex relationship between the gut to disease predisposition and development, heralding the problem and the solution to disease pathology. Human studies of new drug molecules are typically performed in healthy volunteers and their specific disease indication. Approved drugs, however, are used by patients with diverse disease backgrounds. Here, we review the current literature of the gastrointestinal tract reacting to systemic disease pathology that elicits physiological and functional changes that consequently affect oral drug product performance

Shaping the future: recent advances of 3D printing in drug delivery and healthcare

Introduction: Three-dimensional (3D) printing is a relatively new, rapid manufacturing technology that has found promising applications in the drug delivery and medical sectors. Arguably, never before has the healthcare industry experienced such a transformative technology. This review aims to discuss the state of the art of 3D printing technology in healthcare and drug delivery. Areas covered: The current and future applications of printing technologies within drug delivery and medicine have been discussed. The latest innovations in 3D printing of customized medical devices, drug-eluting implants, and printlets (3D-printed tablets) with a tailored dose, shape, size, and release characteristics have been covered. The review also covers the state of the art of 3D printing in healthcare (covering topics such as dentistry, surgical and bioprinting of patient-specific organs), as well as the potential of recent innovations, such as 4D printing, to shape the future of drug delivery and to improve treatment pathways for patients. Expert opinion: A future perspective is provided on the potential for 3D printing in healthcare, covering strategies to overcome the major barriers to integration that are faced today

Effect of Food and an Animal’s Sex on P-Glycoprotein Expression and Luminal Fluids in the Gastrointestinal Tract of Wistar Rats

The rat is one of the most commonly used animal models in pre-clinical studies. Limited information between the sexes and the effect of food consumption on the gastrointestinal (GI) physiology, however, is acknowledged or understood. This study aimed to investigate the potential sex differences and effect of food intake on the intestinal luminal fluid and the efflux membrane transporter P-glycoprotein (P-gp) along the intestinal tract of male and female Wistar rats. To characterise the intestinal luminal fluids, pH, surface tension, buffer capacity and osmolality were measured. Absolute P-gp expression along the intestinal tract was quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). In general, the characteristics of the luminal fluids were similar in male and female rats along the GI tract. In fasted male rats, the absolute P-gp expression gradually increased from the duodenum to ileum but decreased in the colon. A significant sex difference (p < 0.05) was identified in the jejunum where P-gp expression in males was 83% higher than in females. Similarly, ileal P-gp expression in male rats was approximately 58% higher than that of their female counterparts. Conversely, following food intake, a significant sex difference (p < 0.05) in P-gp expression was found but in a contrasting trend. Fed female rats expressed much higher P-gp levels than male rats with an increase of 77% and 34% in the jejunum and ileum, respectively. A deeper understanding of the effects of sex and food intake on the absorption of P-gp substrates can lead to an improved translation from pre-clinical animal studies into human pharmacokinetic studies

Sex-Dependence in the Effect of Pharmaceutical Excipients: Polyoxyethylated Solubilising Excipients Increase Oral Drug Bioavailability in Male but not Female Rats

It is known that males and females respond differently to medicines and that differences in drug behaviour are due to inter-individual variability and sex specificity. In this work, we have examined the influence of pharmaceutical excipients on drug bioavailability in males and females. Using a rat model, we report that a portfolio of polyoxyethylated solubilising excipients (polyethylene glycol 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increase ranitidine bioavailability in males but not in females. The in vivo sex and excipient effects were reflected in vitro in intestinal permeability experiments using an Ussing chamber system. The mechanism of such an effect on drug bioavailability is suggested to be due to the interaction between the excipients and the efflux membrane transporter P-glycoprotein (P-gp), whose expression in terms of gene and protein levels were inhibited by the solubilising agents in male but not in female rats. In contrast, the non-polyoxyethylated excipient, Span 20, significantly increased ranitidine bioavailability in both males and females in a non-sex-dependent manner. These findings have significant implications for the use of polyoxyethylated solubilising excipients in drug formulation in light of their sex-specific modulation on the bioavailability of drugs that are P-gp substrates. As such, pharmaceutical research is required to retract from a ‘one size fits all’ approach and to, instead, evaluate the potential impact of the interplay between excipients and sex on drug effect to ensure effective pharmacotherapy

Prandial state and biological sex modulate clinically relevant efflux transporters to different extents in Wistar and Sprague Dawley rats

P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) are clinically relevant efflux transporters implicated in the oral absorption of many food and drug substrates. Here, we hypothesised that food intake could influence protein and mRNA intestinal expression of P-gp/abcb1a, BCRP/abcg2, and MRP2/abcc2 differently in male and female Wistar and Sprague Dawley rats. To test this hypothesis, we used enzyme-linked immunosorbent assay (ELISA) and real-time polymerase chain reaction (PCR) to quantify the protein and mRNA intestinal expression of these transporters, respectively. Our study found food and sex differences in P-gp expression, whereby in the fed state P-gp expression decreased in male Wistar rats, but P-gp expression increased in females. In the fed state, BCRP expression increased in both male and female Wistar rats, compared with the fasted state. In contrast, no sex differences or food effect differences were seen in Sprague Dawley rats for P-gp and BCRP expression. On the other hand, in the fed state, MRP2 expression was higher in male and female Wistar and Sprague Dawley rats when compared with the fasted state. Sex differences were also observed in the fasted state. Overall, significant strain differences were reported for P-gp, BCRP and MRP2 expression. Strong to moderate positive linear correlations were found between ELISA and PCR quantification methods. ELISA may be more useful than PCR as it reports protein expression as opposed to transcript expression. Researchers must consider the influence of sex, strain and feeding status in preclinical studies of P-gp, BCRP and MRP2 drug substrates

Gastrointestinal Tracking and Gastric Emptying of Coated Capsules in Rats with or without Sedation Using CT imaging

Following oral administration, gastric emptying is often a rate-limiting step in the absorption of drugs and is dependent on both physiological and pharmaceutical factors. To guide translation into humans, small animal imaging during pre-clinical studies has been increasingly used to localise the gastrointestinal transit of solid dosage forms. In contrast to humans, however, anaesthesia is usually required for effective imaging in animals which may have unintended effects on intestinal physiology. This study evaluated the effect of anaesthesia and capsule size on the gastric emptying rate of coated capsules in rats. Computed tomography (CT) imaging was used to track and locate the capsules through the gastrointestinal tract. Two commercial gelatine mini-capsules (size 9 and 9h) were filled with barium sulphate (contrast agent) and coated using Eudragit L. Under the effect of anaesthesia, none of the capsules emptied from the stomach. In non-anaesthetised rats, most of the size 9 capsules did not empty from the stomach, whereas the majority of the smaller size 9h capsules successfully emptied from the stomach and moved into the intestine. This study demonstrates that even with capsules designed to empty from the stomach in rats, the gastric emptying of such solid oral dosage forms is not guaranteed. In addition, the use of anaesthesia was found to abolish gastric emptying of both capsule sizes. The work herein further highlights the utility of CT imaging for the effective visualisation and location of solid dosage forms in the intestinal tract of rats without the use of anaesthesia

3D printing of drug-loaded gyroid lattices using selective laser sintering

Three-dimensional printing (3DP) is gaining momentum in the field of pharmaceuticals, offering innovative opportunities for medicine manufacture. Selective laser sintering (SLS) is a novel, high resolution and single-step printing technology that we have recently introduced to the pharmaceutical sciences. The aim of this work was to use SLS 3DP to fabricate printlets (3D printed tablets) with cylindrical, gyroid lattice and bi-layer structures having customisable release characteristics. Paracetamol-loaded constructs from four different pharmaceutical grade polymers including polyethylene oxide, Eudragit (L100-55 and RL) and ethyl cellulose, were created using SLS 3DP. The novel gyroid lattice structure was able to modulate the drug release from all four polymers. This work is the first to demonstrate the feasibility of using SLS to achieve customised drug release properties of several polymers, in a swift, cost-effective manner, avoiding the need to alter the formulation composition. By creating these constructs, it is therefore possible to modify drug release, which in practice, could enable the tailoring of drug performance to the patient simply by changing the 3D design