Impact of gastrointestinal physiology on drug absorption in special populations––An UNGAP review

Stillhart, Cordula; Vučićević, Katarina; Augustijns, Patrick; Basit, Abdul W.; Batchelor, Hannah; Flanagan, Talia; Gesquiere, Ina; Greupink, Rick; Keszthelyi, Dániel; Koskinen, Mikko; Madla, Christine M.; Matthys, Christophe; Miljuš, Goran; Mooij, Miriam G.; Parrott, Neil; Ungell, Anna‐Lena; Wildt, Saskia N. de; Orlu, Mine; Klein, Sandra; Müllertz, Anette

doi:10.1016/j.ejps.2020.105280

Cited by 162 publications

(125 citation statements)

References 368 publications

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“…In the gastrointestinal (GI) tract, food and its subsequent digestion products can affect drug absorption by changing the luminal fluid environment itself or by physically or chemically interacting with the drug [3]. In addition to food, drug pharmacokinetics can be significantly affected by sex, as numerous studies have shown that males and females can respond differently to medicines [4]. A prominent example is digoxin, a P-glycoprotein (P-gp) substrate, which has shown higher mortality rates among women patients when compared with males for the treatment of heart failure [5].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…Interestingly, whilst the gut microbiome clearly plays a role in hormone metabolism, a number of studies have found a role for hormones in shaping gut microbiome composition, elucidating a bidirectional relationship [31,33]. From a clinical viewpoint, it is anticipated that microbiome metabolism could affect systemic drug exposure and thus lead to inter-individual variations in PK [34][35][36]. Progesterone, MPA, and LNG are known to show such inter-patient variations, a challenge that may make the selection of dosage regimens difficult.…”

Section: Resultsmentioning

confidence: 99%

Progestogens Are Metabolized by the Gut Microbiota: Implications for Colonic Drug Delivery

et al. 2020

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Following oral administration, the bioavailability of progestogens is very low and highly variable, in part due to metabolism by cytochrome P450 enzymes found in the mucosa of the small intestine. Conversely, the mucosa in the colon contains much lower levels of cytochrome P450 enzymes, thus, colonic delivery of progestogens may be beneficial. Microbiota in the colon are known to metabolize a great number of drugs, therefore, it is important to understand the stability of these hormones in the presence of colonic flora before developing formulations. The aim of this study was to investigate the stability of three progestogens: progesterone, and its two synthetic analogues, medroxyprogesterone acetate (MPA) and levonorgestrel (LNG), in the presence of human colonic microbiota. Progesterone, MPA, and LNG were incubated in mixed fecal inoculum (simulated human colonic fluid) under anerobic conditions. Progesterone was completely degraded after 2 h, whereas levels of MPA and LNG were still detectable after 24 h. The half-lives of progesterone, MPA, and LNG in fecal inoculum were 28, 644, and 240 min, respectively. This study describes the kinetics of colonic microbial metabolism of these hormones for the first time. MPA and LNG show promise for delivery to the colon, potentially improving pharmacokinetics over current oral delivery methods.

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“…The influence of critical illness, through the inflammatory response, on the activity of drug transporters and metabolizing enzymes located at the gut mucosa is well recognized 20,21 . Generally, there is a cytokine‐driven decrease in transporter gene and protein expression, with some alterations in metabolizing enzymes (some increasing and others decreasing in expression) 17 . So the assumption that oral drug bioavailability is unchanged in the critically ill patient compared with data derived in healthy individuals is inaccurate.…”

Section: Influence Of Critical Illness On Gut Functionmentioning

confidence: 99%

“…In those with gut dysfunction or systemic disease with an impact on the gut, the potential exists for significantly altered drug absorption. The knowledge about GI physiologic dysfunction and its influence on drug bioavailability remains incomplete, especially for acutely ill patients, although some data have been generated, for example, with gastric bypass 16,17 . Following bypass, the documented anatomic and physiologic alterations impact drug disposition with bioavailability increased, decreased, or unchanged, depending on the medication 16,17 .…”

Section: Influence Of Critical Illness On Gut Functionmentioning

confidence: 99%

Enteral Medication for the Tube‐Fed Patient: Making This Route Safe and Effective

Boullata

2020

Nut in Clin Prac

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The administration of medication through an enteral access device requires important forethought. Meeting a patient's therapeutic needs requires achieving expected drug bioavailability without increasing the risk for toxicity, therapeutic failure, or feeding tube occlusion. Superimposing gut dysfunction, critical illness, or enteral nutrition–drug interaction further increases the need for a systematic approach to prescribing, evaluating, and preparing a drug for administration through an enteral access device. This review will explain the fundamental factors involved in drug bioavailability through the gut, address the influencing considerations for the enterally fed patient, and describe best practices for enteral drug preparation and administration.

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Impact of gastrointestinal physiology on drug absorption in special populations––An UNGAP review

Cited by 162 publications

References 368 publications

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

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

Progestogens Are Metabolized by the Gut Microbiota: Implications for Colonic Drug Delivery

Enteral Medication for the Tube‐Fed Patient: Making This Route Safe and Effective

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