Effect of uremic serum and uremic toxins on drug metabolism in human microsomes.

There is increasing evidence that renal impairment modifies nonrenal drug clearance through drug metabolizing cytochrome P450 (CYP) enzymes. In this study, the direct inhibitory effect of serum from chronic renal failure (CRF) patients receiving dialysis was evaluated in CYP3A4 (testosterone) and CYP2B6 (bupropion) metabolism assays. Human liver microsomes were incubated with ultrafiltered serum collected pre- and post-hemodialysis from ten CRF patients. Additionally, several uremic toxins were evaluated in the CYP3A4 assay. In only three patients was there a significant decrease or increase in testosterone or bupropion metabolism post-dialysis. Urea, mannitol, guanidine, homocysteine, uridine and creatinine had no effect on CYP3A4 metabolism. CMPF, hippuric acid and p-cresol had IC50 values that fell within CRF patient plasma concentrations. The IC50 values for indoxyl sulfate and indole-3-acetic acid were greater than CRF plasma concentrations. The lack of a consistent effect on CYP3A4 or CYP2B6 metabolism by uremic serum may be due in part to the frequency of hemodialysis in these patients which reduced the accumulation of uremic toxins. CMPF, hippuric acid and p-cresol have the ability to inhibit CYP3A4 metabolism at clinical concentrations which may correspond to reports of changes in hepatic metabolism in some CRF patients.

Gastrointestinal phosphate handling in CKD and its association with cardiovascular disease.

Increases in serum concentrations of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23) and ultimately phosphate and decreases in 1,25-dihydroxyvitamin D level are thought to play a central role in the progressive nature of kidney disease and the development of cardiovascular disease in patients with chronic kidney disease. The initial changes in PTH and FGF-23 levels are adaptive to maintain serum phosphate concentration and phosphate load within defined levels by increasing urinary excretion of phosphate. Less well appreciated is the unanticipated finding that absorption of phosphate from the gastrointestinal tract is not downregulated in chronic kidney disease. This maladaptive response maintains higher levels of phosphate absorption, thereby contributing to the phosphate burden. Moreover, in response to a low-phosphate diet, as often is prescribed to such patients, gut phosphate absorption may be enhanced, undermining the potential beneficial effects of this intervention. Given the poor response to limiting phosphate intake and the use of phosphate binders, we suggest that research efforts be oriented toward better understanding of the factors that affect phosphate absorption in the gastrointestinal tract and the development of agents that directly inhibit phosphate transporters in the small intestine and/or their associated binding proteins.

Characterization of hepatic cytochrome p4503A activity in patients with end-stage renal disease.

BACKGROUND: The cytochrome p450 (CYP) oxidative enzyme system, located primarily in the liver and small intestine, is responsible for metabolism and detoxification of numerous endogenous and exogenous substances. The most abundant CYP enzyme, CYP3A, is known to be involved in the metabolism of more than 200 commonly used medications. In experimental models of renal failure, both hepatic function and CYP enzyme content are reduced; however, direct evidence in humans is lacking. Evaluation of drug metabolism in patients with end-stage renal disease is important because these patients use a large number of medications and are at risk of adverse reactions and drug-drug interactions. METHODS: We measured hepatic CYP3A activity at baseline and after rifampin (INN, rifampicin) enzyme induction in 12 patients with end-stage renal disease and 12 healthy, age-matched controls. Hepatic CYP3A phenotype was characterized with the erythromycin breath test, and enzyme induction capacity was evaluated with a short course of rifampin (600 mg/d for 6 days). RESULTS: The end-stage renal disease group had 28% lower baseline erythromycin breath test values than controls (P <.05); however, enzyme induction capacity after rifampin administration was similar between groups (P =.70). CONCLUSION: The findings suggested that one mechanism by which patients with end-stage renal disease are at increased risk of drug toxicity is reduced activity of the CYP3A enzyme pathway.

Effect of center- versus patient-specific factors on variations in dialysis adequacy.

Efforts to improve the delivery of hemodialysis have focused mostly on identifying patient-related factors that lead to inadequate dialysis. Less consideration has been given to the impact of the dialysis center on adequacy. This study evaluated whether the dialysis facility or individual-level factors were the primary influence on variations in dialysis adequacy. This was a retrospective analysis of 4971 hemodialysis patients in 189 centers with urea reduction ratio (URR) values obtained in the final quarter of 1997. The between-center variation and the within-center correlation in URR values were quantified to determine the contribution of a center effect on variations in adequacy; furthermore, the proportion of variance attributable to the centers' effect and individual-level dialysis covariates were compared. There was a wider between-center variation in mean URR values (SD, 4.8%) than expected if there were no center effect (SD, 2.5%). There was a strong within-center correlation in URR values, measured by the parameter rho, which was only minimally diminished after adjusting for individual-level covariates (adjusted rho, 0.14; P < 0.0001). The variation in URR attributable to the center effect, quantified by R(2), was greater than that related to individual-level dialysis factors (facility- and individual-level dialysis covariates R(2), 23.6 and 11.3%, respectively). Initiatives to improve the delivery of dialysis in patients with end-stage renal disease should be directed at facility policies governing dialysis care, along with patient-specific problems, because center effects have a major influence on dialysis adequacy.