Intestinal Ischemia-Reperfusion Suppresses Biliary Excretion of Hepatic Organic Anion Transporting Polypeptides Substrate

Abstract

-Purpose. Intestinal ischemia-reperfusion (I/R) causes gut dysfunction and promotes multi-organ failure. The liver and kidney can be affected by multi-organ failure after intestinal I/R. Organic anion transporting polypeptides (OATPs) and organic anion transporters (OATs) are recognized in a broad spectrum from endogenous compounds to xenobiotics, including clinically important drugs. Therefore, it is important for understanding the pharmacokinetics to obtain evidence of alterations in OATPs and OATs expression and transport activities. In the present study, we investigated the expression of rat Oatps and Oats after intestinal I/R. Methods. We used intestinal ischemia-reperfusion (I/R) model rats. Real-time PCR and Western blotting were used to assess mRNA and protein expression levels. Plasma concentration and biliary excretion of sulfobromophthalein (BSP), which is used as a model compound of organic anion drugs, were measured after intravenous administration in intestinal I/R rats. Results. Although Oat1 and Oat3 mRNA levels were not altered in the kidney, Oatp1a1, Oatp1b2 and Oatp2b1 mRNA levels in the liver were significantly decreased at 1-6 h after intestinal I/R. Moreover, Oatp1a1 and Oatp2b1 protein expression levels were decreased at 1 h after intestinal I/R. Plasma concentration of BSP, which is a typical substrate of Oatps, in intestinal I/R rats reperfused 1 h was increased than that in sham-operated rats. Moreover, the area under the concentration-time curve (AUC0-90) in intestinal I/R rats reperfused 1 h was significantly increased than that in sham-operated rats. The total clearance (CLtot) and the biliary clearance (CLbile) in intestinal I/R rats reperfused 1 h were significantly decreased than those in sham-operated rats. Conclusions. Oatp1a1 and Oatp2b1 expression levels are decreased by intestinal I/R. The decreases in these transporters cause alteration of pharmacokinetics of organic anion compound. The newly found influence of intestinal I/R on the expression and function of Oatps may be a key to perform appropriate drug therapy.

The role of OATP1A1 in cholestasis and drug-induced toxicity: a systematic review

“…In addition, other factors that can down-regulate Oatp1a1 expression include hyperthyroidism (Engels et al, 2015), high-cholesterol diet (Kawase et al, 2017), caloric restriction (Kulkarni et al, 2013), dysbiosis (Kuno et al, 2016), rheumatoid arthritis (Lin et al, 2017), intestinal ischemia-reperfusion (Maruyama et al, 2013), diabetes (Shuboni-Mulligan et al, 2019), hepatic metastatic tumors (Sun et al, 2006), oxidative stress (Tsujimoto et al, 2013) and polycystic kidney disease (Bezençon et al, 2019). From the available reports, almost all pathological changes down-regulate Oatp1a1 expression.…”