Regulation of paracellular absorption of cimetidine and 5-aminosalicylate in rat intestine.
OBJECTIVE
Isolating the relative contributions of parallel transcellular and paracellular transport to the intestinal absorption of small hydrophilic molecules has proven experimentally challenging. In this report, lumenal appearance of drug metabolite is utilized as a tool to assess the contribution of paracellular transport to the absorption of cimetidine and 5-aminosalicylate (5ASA) in rat small intestine.


METHODS
Steady-state intestinal absorption and elimination of cimetidine and 5ASA were studied in single-pass intestinal perfusions in rats.


RESULTS
Both drugs were metabolized in intestinal epithelia with subsequent metabolite secretion into the intestinal lumen. Jejunal cimetidine absorption decreased with increasing perfusion concentration while the ratio of lumenal metabolite to lumenal drug loss increased. Cimetidine uptake at perfusion concentrations above 0.4 mM resulted in over 80% drug elimination into the jejunal lumen. Inhibition of intracellular metabolism of cimetidine by methimazole did not alter epithelial uptake but totally abolished transepithelial cimetidine flux indicating an elevation of intracellular cimetidine. Similarly, co-perfusion of 5ASA with cimetidine and methimazole totally abolished 5ASA absorption but increased lumenal levels of N-acetyl 5ASA indicating an increase in intracellular uptake of 5ASA.


CONCLUSIONS
Cimetidine and 5ASA absorption across rat jejunal epithelia are exclusively paracellular. Elevation of intracellular cimetidine, inferred from mass balance considerations, restricts paracellular transport of both drugs.
Zhou
S Y
SY
Candidate Synthesis Enhancement and Evaluation, Pfizer Central Research, Groton, Connecticut 06340, USA.
Piyapolrungroj
N
N
Pao
L
L
Li
C
C
Liu
G
G
Zimmermann
E
E
Fleisher
D
D
D000758:Anesthesia; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics; D000897:Anti-Ulcer Agents / Q000493:pharmacokinetics; D001693:Biological Transport, Active / Q000502:physiology; D002851:Chromatography, High Pressure Liquid; D002927:Cimetidine / Q000378:metabolism / Q000493:pharmacokinetics*; D004347:Drug Interactions; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007583:Jejunum / Q000378:metabolism*; D008297:Male; D019804:Mesalamine / Q000493:pharmacokinetics*; D008713:Methimazole / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D019804:Mesalamine; D008713:Methimazole; D002927:Cimetidine