title: Effect of uremic serum and uremic toxins on drug metabolism in human microsomes.
abstract: 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.
authors.affiliation: Division of Drug Safety Research, Food and Drug Administration, Silver Spring, MD, USA. Electronic address: donna.volpe@fda.hhs.gov.
authors.forename: Donna A
authors.initials: DA
authors.lastname: Volpe
authors.affiliation: Division of Drug Safety Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Grainne A
authors.initials: GA
authors.lastname: Tobin
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Tavakkoli
authors.affiliation: School of Pharmacy, University of Maryland, Baltimore, MD, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Dowling
authors.affiliation: School of Medicine, University of Maryland, Baltimore, MD, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Light
authors.affiliation: Division of Drug Safety Research, Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Parker
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D016642:Bupropion / Q000378:metabolism; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000628:therapy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D008875:Middle Aged; D006435:Renal Dialysis; D013739:Testosterone / Q000378:metabolism; D014118:Toxins, Biological / Q000378:metabolism*; D014511:Uremia / Q000378:metabolism*
chemical_list: D014118:Toxins, Biological; D016642:Bupropion; D013739:Testosterone; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Chronic renal failure; Metabolism; Uremic serum; Uremic toxins