비스테로이드성 소염제의 소장 내흡수에서 monocarboxylic acid transporters의 역할

Abstract

이번연구는 Caco-2cell서의 비스테로이드성 소염제의 세포흡수 기전을 찾는 것이다. Caco-2 cell서 Diflunisal, diclofenac, ketoprofen and naproxen 4가지약물은 Benzoic acid에 대해 강한 억제를 나타내며 IC50 는 0.05-0.44다. Ketoprofen and naproxen 두 약물은 Benzoic acid의세포막 투과를 억제하였으며 Ki가 각각 0.38mM과 0.22mM이다. Ketoprofen 과 naproxen 약물은 세포 내 흡수에서 고농도일 때 포화상태에 도달했기에 농도에도 의존하는 것을 알 수 있다. 그리고 ketoprofen은 Benzoic acid와 Lactic acid에 의해 세포 내 축적이 감소된다. 그래서 MCT1가 carboxylic acid 구조를 가진 비스테로이성 소염제의 수송체 라는 것을 알 수 있다. 쥐에서 ketoprofen(1mg/kg)을 각각 benzoic acid(10mg/kg)와 lactic acid(10mg/kg)와 동시경구 투여한 것을 대조군으로 하고 ketoprofen(1mg/kg)만 경구 투여한 것을 통제집단으로 하고 비교했는데 대조군에서의 Cmax와AUC는 감소되고 T1/2와Tmax는 영향이 크게 없었다(P<0.05) Benzoic acid와 lactic acid의 수송체는 monocarboxylic acid transporters다. 그러므로 여기에서 benzoic acid와 lactic acid가 ketoprofen의 흡수를 저해한다는 것을 알 수 있고, ketoprofen의 수송체가 monocarboxylic acid transporters것을 알 수 있다.|The present study aims to investigate the cellular uptake mechanism of Nonsteroidal anti-inflammatory drugs (NSAIDs) in Caco-2 cells. Diflunisal, diclofenac, ketoprofen and naproxen exhibited the strong inhibition effect on the cellular uptake of [14C]-benzoic acid in Caco-2 cells with IC50 values of 0.05 0.44 mM. The inhibition of naproxen and ketoprofen against the membrane transport of [14C]-benzoic acid appeared to be competitive with Ki of 0.22 mM and 0.38 mM, respectively. The membrane permeability of naproxen and ketoprofen was concentration dependent, implying that the cellular uptake pathway of ketoprofen and naproxen was saturable at the high concentration. Furthermore, the cellular accumulation of ketoprofen was significantly reduced in the presence of benzoic acid and L-lactic acid, two known substrates of monocarboxylic acid transporter 1 (MCT1). These results suggest that MCT1 contributes at least in part to a carrier-mediated transport of NSAIDs containing a carboxylic acid moiety across the apical membrane in Caco-2 cells. The present study aims to investigate the intestinal absorption characteristics of ketoprofen in rats. The pharmacokinetic profile of ketoprofen was evaluated following a single p.o. administration of ketoprofen (1mg/kg) to rats in the absence and presence of benzoic acid or lactic acid (2 and 10 mg/kg), the substrates of monocarboxylic acid transporters. Pharmacokinetic profiles of ketoprofen (1 mg/kg) were significantly altered by the concurrent use of benzoic acid or lactic acid (10 mg/kg), compared to the control (given ketoprofen alone). Cmax and AUC of ketoprofen in the presence of benzoic acid or lactic acid (10 mg/kg) were significantly (p<0.05) lower than those from the control group, while there was no significant change in Tmax and terminal plasma half-life (T1/2) of ketoprofen. Those results suggest that ketoprofen shares a common transport pathway with benzoic acid and lactic acid during the intestinal absorption in rats.