Gastrointestinal and Systemic Disposition of Diclofenac under Fasted and Fed State Conditions Supporting the Evaluation of in Vitro Predictive Tools

Mol Pharm. 2017 Dec 4;14(12):4220-4232. doi: 10.1021/acs.molpharmaceut.7b00253. Epub 2017 Jul 7.

Abstract

This study aimed to gain further insight into the gastrointestinal disposition of the weakly acidic BCS class II drug diclofenac and the implications for systemic drug exposure in humans under fasted and fed state conditions. For this purpose, gastrointestinal and blood samples were collected from healthy volunteers after oral intake of a commercially available tablet of the potassium salt of diclofenac (i.e., Cataflam) in different prandial states. Subsequently, these in vivo data served as a reference for the evaluation of in vitro tools with different levels of complexity, i.e., a conventional USP II dissolution apparatus, a modified version of the dynamic open flow through test apparatus, and the TNO gastrointestinal model equipped with the recently developed advanced gastric compartment (TIMagc). In vivo data suggested impaired drug dissolution and/or immediate precipitation in the fasted stomach, linked to the acidity of the gastric environment. Similarly, a vast presence of solid drug material in the stomach was observed under fed state conditions, which could be attributed to a marked delay in intragastric tablet disintegration after drug intake with a meal. Emptying of solid drug from the stomach into the duodenum generally resulted in rapid intestinal drug (re)dissolution in both test conditions, explaining the absence of a food effect on the extent of overall systemic exposure for diclofenac. In vitro tools were found to be capable of predicting in vivo intraluminal (and systemic) disposition of this compound, the extent of which depended on the degree to which the dynamic nature of the gastrointestinal process(es) to be investigated was simulated.

Keywords: TIMagc; USP II dissolution apparatus; biopharmaceutics; dynamic open flow through test apparatus; food effects; gastrointestinal tract; oral drug delivery; pharmacokinetics.

Publication types

  • Evaluation Study

MeSH terms

  • Administration, Oral
  • Adult
  • Biopharmaceutics / instrumentation
  • Biopharmaceutics / methods
  • Diclofenac / administration & dosage
  • Diclofenac / pharmacokinetics*
  • Drug Liberation*
  • Fasting / physiology
  • Female
  • Gastric Emptying / physiology
  • Gastrointestinal Tract / physiology
  • Healthy Volunteers
  • Humans
  • Hydrogen-Ion Concentration
  • In Vitro Techniques / instrumentation
  • In Vitro Techniques / methods*
  • Intestinal Absorption / physiology*
  • Male
  • Postprandial Period / physiology
  • Solubility
  • Tablets
  • Young Adult

Substances

  • Tablets
  • Diclofenac