title: In vivo alterations in drug metabolism and transport pathways in patients with chronic kidney diseases.
abstract: OBJECTIVE
  This study was designed to prospectively evaluate the in vivo activities of drug transporters, metabolizing enzymes, and pharmacokinetics in patients with chronic kidney diseases (CKD) caused by glomerulonephritis and nonglomerular etiologies.
  
  
  METHODS
  A prospective study design.
  
  
  METHODS
  Eighteen adults with CKD.
  
  
  METHODS
  General Clinical Research Center at the University of North Carolina and University of Pittsburgh.
  
  
  RESULTS
  Blood and urine were collected and assayed for fexofenadine (transporter function) as well as flurbiprofen and 4-hydroxyflurbiprofen (CYP2C9 function). CYP3A4 activity was assessed by the erythromycin breath test. In patients with glomerulonephritis, the apparent oral clearance of fexofenadine (representing transporter activity) was 58.8 ± 34.4 L/hour, documenting a 40% reduction compared with previous data in healthy controls. The CYP2C9 pathway (4-hydroxyflurbiprofen formation clearance) was similar in all the patients with CKD and was concordant with previous reports of patients with end-stage renal disease (ESRD) and healthy controls. For flurbiprofen, patients with glomerulonephritis had higher oral clearance than those with nonglomerular CKD, suggesting higher unbound fraction and enhanced metabolism through other (non-CYP2C9) routes. No statistically significant differences in CYP3A4 activity were observed in either group of patients or when compared with results from previous studies of patients with ESRD or healthy controls.
  
  
  CONCLUSIONS
  The current study suggests no statistically significant differences in the in vivo activity of CYP2C9 and CYP3A4 in patients with either glomerulonephritis or nonglomerular CKD. However, there are clinical differences in transporter function as defined by at least a 25% reduction in activity in glomerulonephritis as opposed to healthy controls. A similarity in the in vivo function between patients with glomerulonephritis and ESRD, and between patients with glomerulonephritis and nonglomerular CKD was present despite significant differences in kidney function. Further in vivo and in vitro studies are necessary to fully understand the physiologic and disease-specific nuances that contribute to alterations in drug disposition in patients with kidney diseases.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, Colorado; Division of Nephrology and Hypertension, UNC Kidney Center, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Joy
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Nolin
authors.forename: Brittney V
authors.initials: BV
authors.lastname: Roberts
authors.forename: Mary K
authors.initials: MK
authors.lastname: La
authors.forename: Jinzhao
authors.initials: J
authors.lastname: Wang
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Dooley
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001692:Biological Transport; D001944:Breath Tests; D016022:Case-Control Studies; D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D005260:Female; D005480:Flurbiprofen / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D005921:Glomerulonephritis / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051436:Renal Insufficiency, Chronic / Q000503:physiopathology*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: C065522:4'-hydroxyflurbiprofen; D005480:Flurbiprofen; D016593:Terfenadine; C093230:fexofenadine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CYP2C9; CYP3A4; P-glycoprotein; glomerulonephritis; lupus nephritis; single-dose pharmacokinetics; small vessel vasculitis
references.citation: J Am Soc Nephrol. 2006 Sep;17(9):2363-7
references.pmid: 16899515
references.citation: Br J Clin Pharmacol. 1998 Jun;45(6):525-38
references.pmid: 9663807
references.citation: Drug Metab Dispos. 2008 Apr;36(4):663-9
references.pmid: 18180276
references.citation: Drug Metabol Drug Interact. 2004;20(4):195-217
references.pmid: 15663291
references.citation: Drug Metab Dispos. 2005 Oct;33(10):1477-81
references.pmid: 16014768
references.citation: Clin Pharmacol Ther. 1997 Oct;62(4):365-76
references.pmid: 9357387
references.citation: Drug Metab Dispos. 2001 Mar;29(3):207-12
references.pmid: 11181485
references.citation: J Chromatogr B Analyt Technol Biomed Life Sci. 2010 Feb 1;878(3-4):497-501
references.pmid: 20045385
references.citation: Clin Chem. 1981 Aug;27(8):1397-400
references.pmid: 6168414
references.citation: Annu Rev Pharmacol Toxicol. 2006;46:123-49
references.pmid: 16402901
references.citation: Pharmacotherapy. 2009 Jan;29(1):7-16
references.pmid: 19113793
references.citation: Clin Pharmacol Ther. 1993 Dec;54(6):612-20
references.pmid: 8275616
references.citation: JAMA. 2007 Nov 7;298(17):2038-47
references.pmid: 17986697
references.citation: Clin Pharmacokinet. 1984 Jan;9 Suppl 1:18-26
references.pmid: 6705423
references.citation: Drug Metab Dispos. 2008 Jan;36(1):124-8
references.pmid: 17940133
references.citation: Clin Pharmacol Ther. 2003 May;73(5):475-7
references.pmid: 12732848
references.citation: J Am Soc Nephrol. 2009 Oct;20(10):2269-76
references.pmid: 19696225
references.citation: Clin Pharmacol Ther. 2006 Mar;79(3):218-30
references.pmid: 16513446
references.citation: Clin Pharmacol Ther. 2003 May;73(5):427-34
references.pmid: 12732843
references.citation: Drug Metab Dispos. 2008 Jan;36(1):61-4
references.pmid: 17913796
references.citation: Nat Rev Drug Discov. 2010 Mar;9(3):215-36
references.pmid: 20190787
references.citation: Clin Pharmacol Ther. 1995 Jan;57(1):16-24
references.pmid: 7828377
references.citation: Pharmacotherapy. 1998 Nov-Dec;18(6):1271-6
references.pmid: 9855326
references.citation: Clin Pharmacol Ther. 2003 Nov;74(5):437-47
references.pmid: 14586384
references.citation: J Clin Pharmacol. 1991 Sep;31(9):808-14
references.pmid: 1804864
references.citation: Drug Metab Dispos. 2008 May;36(5):911-5
references.pmid: 18276836
references.citation: Clin J Am Soc Nephrol. 2009 Jan;4(1):39-47
references.pmid: 19073787
references.citation: Nephrol Dial Transplant. 2004 Jul;19(7):1842-8
references.pmid: 15128886
references.citation: Clin Pharmacol Ther. 1974 Mar;15(3):276-82
references.pmid: 4815953
references.citation: Nephron. 1976;16(1):31-41
references.pmid: 1244564
references.citation: Clin Pharmacol Ther. 2002 Dec;72(6):718-28
references.pmid: 12496753
references.citation: J Clin Pharmacol. 2010 Jun;50(6):714-20
references.pmid: 20103693
references.citation: Drug Metab Dispos. 2005 Jul;33(7):963-8
references.pmid: 15821041
references.citation: Ann Pharmacother. 2009 Jun;43(6):1020-7
references.pmid: 19491317
references.citation: J Clin Pharmacol. 2005 Mar;45(3):352-6
references.pmid: 15703370
references.citation: Clin Pharmacol Ther. 2008 Jun;83(6):898-903
references.pmid: 18388866
references.citation: Pharmacol Ther. 2006 Jan;109(1-2):1-11
references.pmid: 16085315
references.citation: Br J Pharmacol. 2002 Dec;137(7):1039-46
references.pmid: 12429576
references.citation: Clin Pharmacol Ther. 2007 Jun;81(6):828-32
references.pmid: 17361125
references.citation: J Am Soc Nephrol. 2008 Jul;19(7):1352-9
references.pmid: 18417721
references.citation: Clin Pharmacol Ther. 2006 Sep;80(3):257-63
references.pmid: 16952492