دانلود رایگان مقاله اثر استئاتوهپاتیت غیر الکلی در فیلتراسیون کلیوی و ترشح آدفوویر

abstract

Background and aims: Adefovir, an acyclic nucleotide reverse transcriptase inhibitor used to treat hepatitis B viral infection, is primarily eliminated renally through cooperation of glomerular filtration with active tubular transport. Nonalcoholic steatohepatitis is a variable in drug disposition, yet the impact on renal transport processes has yet to be fully understood. The goal of this study was to determine the effect of nonalcoholic steatohepatitis on the pharmacokinetics of adefovir in rats given a control or methionine and choline deficient diet to induce nonalcoholic steatohepatitis. Methods: Animals received a bolus dose of 7 mg/kg (35 lCi/kg) [3 H] adefovir with consequent measurement of plasma and urine concentrations. Inulin clearance was used to determine glomerular filtration rate. Results: Methionine and choline deficient diet-induced nonalcoholic steatohepatitis prolonged the elimination half-life of adefovir. This observation occurred in conjunction with reduced distribution volume and hepatic levels of adefovir. Notably, despite these changes, renal clearance and overall clearance were not changed, despite markedly reduced glomerular filtration rate in nonalcoholic steatohepatitis. Alteration of glomerular filtration rate was fully compensated for by a significant increase in tubular secretion of adefovir. Analysis of renal transporters confirmed transcriptional up-regulation of Mrp4, the major transporter for adefovir tubular secretion. Conclusions: This study demonstrates changes to glomerular filtration and tubular secretion that alter pharmacokinetics of adefovir in nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis-induced changes in renal drug elimination processes could have major implications in variable drug response and the potential for toxicity.

4. Discussion

In recent years the prevalence of NAFLD has been steadily increasing, making it the most common liver disease worldwide, and in Western countries, NAFLD incidence is correlated to lifestyle habits [25]. Recent advances indicate that the severe form of NAFLD, NASH, can cause significant alterations in liver transporter expression and xenobiotic pharmacokinetics [14,16,26–29], and can therefore lead to increased susceptibility for adverse drug reactions (ADRs) [13,30–32]. Moreover, recent studies demonstrate that various animal models of NASH also cause significant alterations in the expression of membrane transporters in the kidneys, although no one has demonstrated the functional consequence of these alterations [26,33]. Herein, we found that upregulation of renal efflux transporters involved in luminal secretion may compensate for the decreased GFR frequently observed in liver injury,by supporting the renal secretion of xenobiotics and endogenous metabolites into the urine [17]. We therefore evaluated the influence of modeled NASH on the pharmacokinetics of adefovir, a drug eliminated primarily by kidneys. The plasma concentrations of adefovir showed no significant differences between the normal and NASH groups. Adefovir was rapidly cleared from plasma when administered as an i.v. single bolus dose, with the initial half-life of approximately 15 min, which corresponds with previous studies in mice and rats [34,35] and a terminal elimination half-life of approximately 2 h. While the total clearance of adefovir was not changed in NASH, the contribution of renal excretory pathways to its elimination was markedly altered. The glomerular filtration in the NASH group decreased by about 50%, but this was counterbalanced by a net tubular secretion increase compared to control group, mediated via induction of Mrp4, the major efflux transporter for adefovir. As a consequence, total clearance of adefovir was not changed, but its concentration profiles in urine were different. These data suggest that Mrp4 may be a rate-limiting factor for adefovir tubular secretion, as its induction was able to rescue the potentially decreased renal elimination stemming from GFR changes. In support of this conclusion, increased accumulation of adefovir was recently described in human proximal tubular cells when MRP4 transporter was downregulated by hypoxia [36].