Effects of chronic kidney disease on liver transport: quantitative

42 43 Clinical studies indicate that hepatic drug transport may be altered in chronic kidney 44 disease (CKD). Specifically, uremic solutes associated with CKD have been found to 45 alter the expression and/or activity of hepatocyte transporters in experimental animals 46 and in cultured cells. However, given the complexity and adaptability of hepatic 47 transport, it is not clear whether these changes translate into significant alterations in 48 hepatic transport. In order to directly measure the effect of CKD on hepatocyte transport 49 in-vivo, we conducted quantitative intravital microscopy of transport of the fluorescent 50 organic anion fluorescein in the livers of rats following 5/6 nephrectomy, an established 51 model of CKD. Our quantitative analysis of fluorescein transport showed that the rate of 52 hepatocyte uptake was reduced by approximately 20% in 5/6 nephrectomized rats, 53 consistent with previous observations of Oatp down-regulation. However, the overall 54 rate of transport into bile canaliculi was unaffected, suggesting compensatory changes in 55 Mrp2-mediated secretion. Our study suggests that uremia resulting from 5/6 56 nephrectomy does not significantly impact the overall hepatic clearance of an Oatp 57 substrate. 58 59 60 61 62 63 64 65 66