Carrier-mediated Intestinal Absorption

DI Friedman, GL Amidon. Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats Enalapril and fosinopril. Pharm Res 6(12) 1043-1047, 1989. 

Sinko, P. J., and Balimane, P. V. Carrier-mediated intestinal absorption of valacyclovir, the L-valyl ester prodrug of acyclovir I. Interactions with peptides, organic anions and organic cations in rats. Biopharm. Drug Dispos. 19(4) 209-217, 1998. 

Hu, M. and Amidon, G.L. (1988) Passive and carrier-mediated intestinal absorption components of captopril. Journal of Pharmaceutical Sciences, 77 (12), 1007-1011. 

Single-pass intestinal perfusion studies For evaluatton of intestinal prermeability and lymphatic uptake Predict the exact mechanism of absorption, that is, passive absorption, carrier mediated absorption or active transport Evaluate the P-gp efflux and role of transporters (MRP, BCRP2) in reducing the oral bioavailability of drugs... 

Tamai, I. [Molecular characterization of intestinal absorption of drugs by carrier-mediated transport mechanisms]. Yakugaku Zasshi 1997, 117, 415-434. 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

The advantages of the in situ techniques include an intact blood supply multiple samples may be taken, thus enabling kinetic studies to be performed. A fundamental point regarding the in situ intestinal perfusion method is that the rat model has been demonstrated to correlate with in vivo human data [46 19], Amidon et al. [36] have demonstrated that it can be used to predict absorption for both passive and carrier-mediated substrates. However, the intestinal luminal concentrations used in rat experiments should reflect adequately scaled and clinically relevant concentrations to ensure appropriate permeability determinations [50], There are limitations of the in situ rat perfusion models. The assumption involved in derivation of these models that all drug passes into portal vein, that is drug disappearance reflects drug absorption, may not be valid in some circumstances as discussed below. 

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