[Intestinal absorption and secretion mechanism of carboxylate drugs].
Oral drug delivery is generally the most desirable means of administration, mainly because of patient acceptance, convenience in administration. Intestinal absorption mechanisms of anionic drugs have been mainly explained by the passive diffusion of nonionized compounds. However, several studies have suggested the involvement of specific transporters in intestinal absorption of weak acids including monocarboxylates. (-)-N-(trans-4-Isopropylcyclohexanecarbonyl)-D-phenylalanine (nateglinide) is a oral hypoglycemic agent possessing a carboxyl group and a peptide-type bond in its structure. Although nateglinide quickly reaches the maximal serum concentration after oral administration, nateglinide itself is not transported by PepT1 or MCT1. We demonstrated that nateglinide transport occurs via a single system that is H(+) dependent but is distinct from PepT1 or MCT1. In clinical, patients usually take many kinds of drugs at the same time. Thus, drug-drug interactions involving transporters can often directly affect the therapeutic safety and efficacy of many drugs. However, there have been few studies on food-drug interactions involving transporters. Dietary polyphenols have been widely assumed to be beneficial to human health. Polyphenols are commercially prepared and used as functional foods. We reported that ferulic acid, which is widely used as a functional food, affects the transport of clinical agents. The major dose-limiting toxicity after administration of irinotecan hydrochloride, 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxycamptothecin (CPT-11) is severe diarrhea. We have found that a specific transport system mediates the uptake of active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) across the apical membrane in Caco-2 cells. Baicalin and sulfobromophthatlein inhibit this transporter. Inhibition of this transporter would be a useful means for reducing late-onset diarrhea.
Itagaki
Shirou
S
Laboratory of Clinical Pharmaceutics and Therapeutics, Department of Biopharmaceutical Sciences and Pharmacy, Division of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-ku, Sapporo, Japan. itagaki@pharm.hokudai.ac.jp
D000284:Administration, Oral; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D001562:Benzimidazoles / Q000008:administration & dosage / Q000378:metabolism; D001565:Benzoates / Q000008:administration & dosage / Q000378:metabolism; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000378:metabolism; D003373:Coumaric Acids; D003510:Cyclohexanes / Q000008:administration & dosage / Q000378:metabolism*; D004347:Drug Interactions; D005419:Flavonoids; D018565:Food-Drug Interactions; D055951:Functional Food; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000378:metabolism*; D007408:Intestinal Absorption; D000077146:Irinotecan; D027501:Monocarboxylic Acid Transporters / Q000502:physiology; D000077715:Nateglinide; D010636:Phenols; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D059808:Polyphenols; D000077333:Telmisartan
D000806:Angiotensin-Converting Enzyme Inhibitors; D000972:Antineoplastic Agents, Phytogenic; D001562:Benzimidazoles; D001565:Benzoates; D003373:Coumaric Acids; D003510:Cyclohexanes; D005419:Flavonoids; D007004:Hypoglycemic Agents; D027501:Monocarboxylic Acid Transporters; D010636:Phenols; D059808:Polyphenols; D000077715:Nateglinide; D010649:Phenylalanine; D000077146:Irinotecan; C004999:ferulic acid; D000077333:Telmisartan; D002166:Camptothecin