Colonic absorption of antiepileptic agents.
OBJECTIVE
To evaluate a canine intestinal accessport model to study colonic absorption of drugs. The antiepileptic drugs phenytoin and gabapentin were chosen to study absorption of a lipophilic and hydrophilic compound, respectively.


METHODS
Drug plasma level-time plots were generated subsequent to small intestinal and colonic drug administration of both drugs. The poorly water-soluble phenytoin was administered in two doses to evaluate the impact of dissolution rate limits on colonic absorption. Maximal plasma concentration (Cmax) and area under the plasma level-time curve (AUC) were used to assess the relative contribution of colonic absorption to plasma levels.


RESULTS
Whereas colonic gabapentin AUC and Cmax were only 0.25 and 0.15 of those seen after small intestinal administration, colonic phenytoin AUC and Cmax were one half and equivalent to, respectively, those observed for small intestinal administration. Furthermore, colonic administration of a higher phenytoin dose showed secondary maxima and continued increases in drug plasma levels with time.


CONCLUSIONS
Colonic gabapentin absorption is poor compared with upper intestinal absorption, consistent with membrane transport rate limits to the absorption of this hydrophilic AED. Peak phenytoin plasma levels from colonic and small intestinal administration are comparable, indicating membrane transport does not limit absorption of this lipophilic agent. Continued plasma-level increases from higher phenytoin doses are consistent with dissolution-rate control of drug absorption in the colon. We suggest that colonic absorption provides a greater potential for toxicity from phenytoin overdose as a function of continued drug dissolution than for gabapentin overdose.
Stevenson
C M
CM
Whitehall Robins Health Care, Hammonton, New Jersey, USA.
Kim
J
J
Fleisher
D
D
D000085:Acetates / Q000097:blood / Q000493:pharmacokinetics* / Q000506:poisoning; D000588:Amines; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000506:poisoning; D001692:Biological Transport; D002851:Chromatography, High Pressure Liquid; D003106:Colon / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids; D004285:Dogs; D062787:Drug Overdose; D000077206:Gabapentin; D007322:Instillation, Drug; D007408:Intestinal Absorption; D007421:Intestine, Small / Q000378:metabolism; D010672:Phenytoin / Q000097:blood / Q000493:pharmacokinetics* / Q000506:poisoning; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000927:Anticonvulsants; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D010672:Phenytoin; D000077206:Gabapentin