Drug absorption intestinal mucosa

The lanthaninn teehnique was used to study the epithelial permeability in the rat small intestine (Madara and Trier 1982). Dense lanthanum precipitates in TJ and paracellular spaces were restricted to a subpopulation of villous goblet cells and were not found between villous absorptive cells. These TJ were also permeable to barium, but not to macromolecular tracers such as microperoxidase, eytochrome c and horseradish peroxidase. It was also shown that palmitoylcamitine (PCC) opens TJ in a monolayer of Caco-2 colon carcinoma cells this phenomenon appears to be responsible for the significant enhancement of the absorption of hydrophilic drugs across intestinal mucosa caused by PCC and other long-chain acylcamitines (Hochman, Fix et al. 1994).In an experiment on rats, it was demonstrated that immobilisation stress induced a significant (but reversible) increase in epithelial permeability to the lanthanum tracer (Mazzon, Stumiolo et al. 2002). 

P-glycoprotein (P-gp) works as a transporter at the intestinal mucosa pumping drugs out into the lumen. Absorption of P-gp substrates, such as digoxin, cyclosporine, etc., can be increased by inhibitors of P-gp and reduced by inducers. 

Artursson, P., Cell cultures as models for drag absorption across the intestinal mucosa, Crit. Rev. Ther. Drug Carrier Syst. 1991, 8, 305-330. 

Lennernas, H., Does fluid flow across the intestinal mucosa affect quantitative oral drug absorption Is it time for a reevaluation , Pharm. Res. 

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... 

Lennernas H (1995) Does Fluid Flow Across the Intestinal Mucosa Affect Quantitative Oral Drug Absorption Is It Time for a Re-Evaluation Pharm Res 12 pp 1573-1582. 

The Intestinal Mucosa as a Physical and Biochemical Barrier to Drug Absorption... 

When a drug has dissolved in the GI fluids and is present in solution at the site of absorption it has to pass a biological barrier, that is, the enterocytes lining the gut wall, in order to be absorbed into the body. The absorptive flux (J) can be described as a function of the permeability of the intestinal mucosa to the drug (Peff), the surface area available for absorption (SA), and the concentration gradient (AC) across the mucosa (e.g., [6], Eq. 2)... 

The concentration gradient across the intestinal mucosa, being the driving force for passive absorption, is affected by the thermodynamic solubility and dissolution rate of the drug in the intestinal fluids as described earlier. 

There have been sustained efforts in recent years to use the carrier systems of the brush-border membrane of intestinal mucosa to increase absorption of orally administered drugs [29] [30]. One system of particular interest is the intestinal peptide carrier (hPEPTl) whose physiological function is the absorption of di- and tripeptides and whose xenobiotic substrates include /3-lactam antibiotics, renin inhibitors, and angiotensin-converting enzyme (ACE) inhibitors [31]. 

The oral absorption of amprenavir is rapid, and peak concentrations are reached between 1 and 2h administration of both amprenavir and fosamprenavir with food is not a concern. Fosamprenavir is dephosphorylated to amprenavir in intestinal mucosa. Amprenavir is 90% bound to plasma protein with most to ai-acid glycoprotein. It is metabolized by the cytochrome P-450 system, CYP3A4, in the liver, and more than 90% of the drug is excreted after its metabolism in feces. In combination with other antiretroviral agents, amprenavir/fosamprenavir are indicated for the treatment of HIV infection. 

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