Toward an Increased Understanding of the Barriers to Colonic Drug Absorption in Humans: Implications for Early Controlled Release Candidate Assessment

Abstract

The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) < 50%). There was a clear correlation between in vitro Caco-2 permeability and Frel(colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

Translating Human Effective Jejunal Intestinal Permeability to Surface-Dependent Intrinsic Permeability: a Pragmatic Method for a More Mechanistic Prediction of Regional Oral Drug Absorption

“…It has been suggested that due to a reduced SA and higher abundance of tight junctions (i.e. assumed smaller paracellular area) in the colonic membrane, intestinal permeability and possibly absorption should be reduced compared to that in the SI (4,5,22,25,66,67). This was appropriately captured when the predictions were made using P eff,int , estimated by both M2 and M3, without affecting the overall f abs predictions (Figs.…”

“…BCS class 2 and 4 drugs. For those drugs, accounting for the GI physiological factors affecting the solubility, dissolution and precipitation along the GI tract is absolutely necessary, especially when it comes to the prediction and understanding of their regional intestinal absorption (4,25,(83)(84)(85). However, for our simulations, that assumption seemed reasonable as the majority of the drugs listed in Table II can be classified as highly soluble (BCS classes 1 and 3), with the exception of furosemide, which is poorly soluble weak acid (pKa=3.9), yet its solubility is expected to be high at the intestinal pH range (6-7.4) (85,86).…”

“…Given that such values were determined mostly using open perfusion systems, their comparison with the ones obtained from the double-balloon technique is limited (4,5). Recent works have highlighted the necessity for regional P eff estimates in humans, which are of particular interest during early stages of drug and formulation development (4,5,21,25). Yet, due to the vast economic cost associated with clinical perfusion studies, further investigations on regional P eff determination might be limited in the near future.…”

In vivo Studies for Drug Development via Oral Delivery: Challenges, Animal Models and Techniques

“…Sjogren et al has summarized the biopharmaceutical factors influencing the in vivo drug performance (pharmacokinetics/and or dynamic) in respective preclinical models like pig, dog, mouse, rat and also in human [35]. In vitro testing of significant barriers to intestinal absorption in humans, specifically permeability and solubility of a drug, are recommended in the early assessment of colonic absorption [44]. The lack of successful attempts to predict gastrointestinal absorption of poorly soluble drugs creates the need for a better understanding of the in vivo GI process, which includes the changing physiological conditions, the fed versus fasted state, and the effect of pharmaceutical product characteristics.…”

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

“…The mechanism proposed for this phenomenon is an increased intestinal availability (F G ) due to a decreased intestinal first-pass metabolism as a result of the lower abundance of CYP3A enzymes in the distal gastrointestinal (GI) tract, where most of the drug contained in the MR formulation is likely to be released and absorbed (21)(22)(23)(24). Another interesting outcome of the study was the observed trend to over predict f abs of MR formulations belonging to BCS Classes 2 and 3 (21,25). This over prediction was attributed to an overestimation of the colonic absorption due to the PBPK approach employed for the study.…”