Intestinal drug absorption fraction absorbed

For the majority of drugs, the preferred administration route is by oral ingestion which requires good intestinal absorption of drug molecules. Intestinal absorption is usually expressed as fraction absorbed (FA), expressing the percentage of initial dose appearing in a portal vein [15]. 

The CAT model considers passive absorption, saturable absorption, degradation, and transit in the human small intestine. However, the absorption and degradation kinetics are the only model parameters that need to be determined to estimate the fraction of dose absorbed and to simulate intestinal absorption kinetics. Degradation kinetics may be determined in vitro and absorption parameters can also be determined using human intestinal perfusion techniques [85] therefore, it may be feasible to predict intestinal absorption kinetics based on in vitro degradation and in vivo perfusion data. Nevertheless, considering the complexity of oral drug absorption, such a prediction is only an approximation. 

Refinement and expansion of these steady-state mass balance approaches has led to the development of dynamic models which allow for estimation of the fraction absorbed as a function of time and can therefore be used to predict the rate of dmg absorption [37], These compartmental absorption and transit models (CAT) models have subsequently been used to predict pharmacokinetic profiles of drugs on the basis of in vitro dissolution and permeability characteristics and drug transit times in the intestine [38],... 

Lennernas s group at Uppsala has performed extensive studies to confirm the validity of this in vivo experimental set-up at assessing the rate and the extent of drug absorption. Recovery of PEG 4000 (a non-absorbable marker) is more than 95%, which indicates that the absorption barrier is intact. In addition, maintenance of functional viability of the mucosa during perfusion has been demonstrated by the rapid transmucosal transport of D-glucose and L-leucine. Estimation of absorption half-lives from the measured Pefr agree well with half-lives derived from oral dose studies in humans (i.e. physiologically realistic half-lives). Human Peff estimates are well correlated with the fraction absorbed in humans, and served as the basis for BCS development, and hence the technique is ultimately the benchmark by which other in situ intestinal perfusion techniques are compared. The model has been extensively used to... 

This theory was further explored in an anaesthetised pig model, which facilitated portal vein and bile sampling [86], However, the hepatic extraction ratio and the biliary clearance of fexofenadine were unaffected by verapamil in the pig model. The question as to why verapamil/ketoconazole increase the fraction absorbed (i.e. based on appearance kinetics) and yet the fraction absorbed estimated on the basis of disappearance kinetics (i.e. /err) for the intestinal segment appears unchanged remains to be explored and most likely reflect multiple interplay between absorptive and efflux drug transporters in the intestinal tissue. 

Most psychotropic medications are given orally and are absorbed after dissolution, primarily in the small intestine. The rate of absorption (expressed as a rate constant Ka [1/h]) is usually passive and obeys first-order principles, meaning that the rate of absorption is dependent on the amount of drug at the site of absorption, with a constant fraction absorbed per unit of time. 

The permeability class boundary is based indirectly on the extent of absorption (fraction of dose absorbed, not systemic BA) of a drug substance in humans and directly on measurements of the rate of mass transfer across human intestinal membrane. Alternatively, nonhuman systems capable of predicting the extent of drug absorption in humans can be used (e.g., in vitro epithelial cell culture methods). In the absence of evidence suggesting instability in the gastrointestinal tract, a drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose. 

Absorption rate coefficients and permeability values obtained through different systems, i.e. in vitro or in situ, finally are determined with the objective in mind of predicting the fraction of a dose that will be absorbed through the intestine when the drug is orally administered. In order to use the data obtained in those systems it is essential to validate them properly. The present section reviews the capability of the parameters representatives of the absorption determining with different techniques to predict in vivo drug absorption in absence of any limited step (as dissolution or solubility) by means of the previously described model and Eq. (16). In particular, the absorption rate constant obtained with an in situ close loop assay, permeability through Caco-2 cell lines, and PAM PA models have been examined. 

Several parameters relate to the prediction of absorption. One of the parameters used to quantify Human Intestinal Absorption (HIA) is the fraction absorbed (%F), which is defined as the mass absorbed divided by the total mass of the given drug dose ... 

The rapid evaluation of the intestinal membrane permeability of drugs represents a continuing challenge. Human intubation studies have been used to measure jejeunal effective permeability of a number of drugs, and these measurements have been compared with the extent of drug absorption. It can be seen from Figure 4.6 that the expected fraction absorbed exceeds 95% for drugs with a jejeunal permeability of more than 2-4 x 10 cm/sec (29). 

Figure 2. Estimation of DCS class based on the GastroPlus software of SimulationPlus. Based on the dimensionless Dose, Absorption and Dissolution Numbers, drugs can be defined as DCS Class 1 (A), 11 (B), 111 (C) and IV (D) based solely on structural information. The program gives predicted values for solubility, pKa and effective human intestinal permeability in order to suggest a fraction absorbed into the portal vein. (See color insert after Index.)...

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