Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities.
OBJECTIVE
This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities.


METHODS
In vitro dissolution--in vivo absorption analysis was conducted on four formulations of each ranitidine HCl, metoprolol tartrate, and piroxicam to yield apparent and "true" human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined.


RESULTS
In vitro dissolution--in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [kp = 0.225 hr-1, 0.609 hr-1, and 9.00 hr-1 for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine.


CONCLUSIONS
There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.
Polli
J E
JE
School of Pharmacy, University of Maryland, Baltimore 21201, USA. polli@pharmacy.ab.umd.edu
Ginski
M J
MJ
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D018938:Caco-2 Cells / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption; D008790:Metoprolol / Q000493:pharmacokinetics*; D008954:Models, Biological; D010539:Permeability / Q000187:drug effects; D010894:Piroxicam / Q000493:pharmacokinetics*; D011899:Ranitidine / Q000493:pharmacokinetics*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D000959:Antihypertensive Agents; D010894:Piroxicam; D011899:Ranitidine; D008790:Metoprolol