The prominent impairment of liver/intestinal cytochrome P450 and intestinal drug transporters in sepsis-induced acute kidney injury over acute and chronic renal ischemia, a mouse model comparison

Abstract

Drug dosing adjustment in sepsis-induced acute kidney injury (sepsis-AKI) is currently adjusted based on renal function. Sepsis is a multiorgan injury, and thus, drug metabolism in sepsis-AKI might be interfered by non-renal factors such as changes in functions of drug-metabolizing enzymes in the liver and functions of intestinal drug transporters. We compared the defect on mouse CYP3A11 (human CYP3A4 representative) in liver and intestine along with several intestinal drug transporters (MDR1a, MRP2, and OATP3) in three mouse models; chronic ischemic reperfusion injury (Chr I/R; 4-week), acute ischemic reperfusion injury (Acute I/R; 24-h), and cecal ligation and puncture (CLP; 24-h) as representative of sepsis-AKI. Decreased expression of CYP3A11 and drug transporters was demonstrated in all models. Among these models, sepsis-AKI had the least severe renal injury (increased BUN and Scr) with the most severe liver injury (increased ALT and changes in liver histopathology), the most severe intestinal leakage (increased serum (1→3)-β-D-glucan) and the highest increase in serum IL-6. A reduced expression and activity of liver and intestinal CYP3A11 along with intestinal efflux-drug transporter expressions (MDR1a and MRP2), but not drug uptake transporter (OATP3), was predominant in sepsis-AKI compared with acute I/R. Additionally, a reduction of CYP3A4 expression with IL-6 was demonstrated on HepG2 cells implying a direct injury of IL-6 on human liver cells. Differences in drug metabolism were reported between sepsis-AKI and ischemic-AKI confirming that drug dosing adjustment in sepsis-AKI depends not just only on renal function but also on several non-renal factors. Further studies are warranted.

Current trends in drug metabolism and pharmacokinetics

“…It was found that the plasma theophylline concentration was significantly increased in rats with CKD 206 . Moreover, a reduced metabolism of midazolam could be observed in rats with acute kidney injury (AKI) 207 .…”

“…Among them, the effects of polymicrobial sepsis on the activity and gene expression of hepatic microsomal CYP450 have attracted considerable attention due to their potential disease–drug interactions in clinical therapy. It has been reported that the major hepatic CYP isoforms CYP1A1, 1A2, 2B1, 2E1 were down-regulated during polymicrobial sepsis 208 , 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224. Moreover, results from mechanistic studies show that nitric oxide (NO) and the AhR play key potential roles in down-regulation of hepatic CYP during sepsis 225 , 226 .…”

Acute Kidney Injury Induced Lupus Exacerbation Through the Enhanced Neutrophil Extracellular Traps (and Apoptosis) in Fcgr2b Deficient Lupus Mice With Renal Ischemia Reperfusion Injury

“…In parallel, acute kidney injury (AKI) is the common health care problem worldwide, which is mainly caused by ischemia (26) that was often represented by renal ischemia reperfusion injury (I/R) animal model (27,28). As such, renal ischemia induces accumulation of immune cells, including neutrophils, as a response to the injury (29)(30)(31) and the injury also causes apoptosis (and necrosis) in renal parenchymal cells and neutrophils (32,33).…”

Prominent Indomethacin-Induced Enteropathy in Fcgriib Defi-cient lupus Mice: An Impact of Macrophage Responses and Immune Deposition in Gut

“…Perhaps, NSAIDs induced uremia and uremia-induced inflammation exacerbates lupus activity [34,35]. However, NSAIDs nephropathy might not be a main lupus exacerbating factor in NSAIDs-mouse model because (i) the uremia in NSAIDs model (no obvious renal histological damage) is less severe than other direct renal damage models (ischemia and bilateral nephrectomy) [61,62] and (ii) endotoxemia from uremia (an indirect mucosal damage) is less severe than the endotoxemia from the direct gut mucosal injury caused by NSAIDs [63,64],…”