title: Cyclophosphamide and 4-hydroxycyclophosphamide pharmacokinetics in patients with glomerulonephritis secondary to lupus and small vessel vasculitis.
abstract: OBJECTIVE
  Cyclophosphamide, the precursor to the active 4-hydroxycyclophosphamide, is used in active glomerulonephritis despite limited pharmacokinetics data. The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide were evaluated. The influence of laboratory and pharmacogenomic covariates on pharmacokinetics was evaluated as a secondary aim.
  
  
  METHODS
  Glomerulonephritis patients (n = 23) participated in a pharmacokinetic evaluation. Blood was serially collected and assayed for cyclophosphamide and 4-hydroxycyclophosphamide by LC/MS methods. Kidney function, serum albumin and polymorphisms in drug metabolism or transport genes were evaluated. Analyses included non-compartmental pharmacokinetics and parametric and non-parametric statistics.
  
  
  RESULTS
  The mean area under the plasma concentration-time curve (AUC(0,∞)) data were 110,100 ± 42,900 ng ml(-1) h and 5388 ± 2841 ng ml(-1) h for cyclophosphamide and 4-hydroxycyclophosphamide, respectively. The mean metabolic ratio was 0.06 ± 0.04. A statistically significant relationship was found between increased serum albumin and increased half-life (0.584, P = 0.007, 95% CI 0.176, 0.820) and a borderline relationship with AUC(0,∞) (0.402, P = 0.079, 95% CI -0.064, 0.724) for 4-hydroxycyclophosphamide. Covariate relationships that trended toward significance for cyclophosphamide included decreased serum albumin and increased elimination rate constant (-0.427, P = 0.061, 95% CI 0.738, 0.034), increased urinary protein excretion and increased AUC(0,∞) (-0.392, P = 0.064, 95% CI -0.699 to 0.037), decreased C(max) (0.367, P = 0.085, 95% CI -0.067, 0.684) and decreased plasma clearance (-0.392, P = 0.064, 95% CI -0.699, 0.037). CYP2B6*9 variants vs. wildtype were found to have decreased elimination rate constant (P = 0.0005, 95% CI 0.033, 0.103), increased V(d) (P = 0.0271, 95% CI -57.5, -4.2) and decreased C(max) (P = 0.0176, 95% CI 0.696, 6179) for cyclophosphamide. ABCB1 C3435T variants had a borderline decrease in cyclophosphamide elimination rate constant (P = 0.0858; 95% CI -0.005, 0.102).
  
  
  CONCLUSIONS
  Pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in patients with lupus nephritis and small vessel vasculitis are similar. Clinical and pharmacogenetic covariates alter disposition of cyclophosphamide and 4-hydroxycyclophosphamide. Clinical findings of worsened glomerulonephritis lead to increased exposure to cyclophosphamide vs. the active 4-hydroxycyclophosphamide, which could have relevance in terms of clinical efficacy. The CYP2B6*9 and ABCB1 C3435T polymorphisms alter the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in glomerulonephritis.
authors.affiliation: Division of Nephrology and Hypertension, UNC Kidney Center, University of North Carolina School of Medicine, Chapel Hill, USA. melanie_joy@med.unc.edu
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Joy
authors.forename: Mary
authors.initials: M
authors.lastname: La
authors.forename: Jinzhao
authors.initials: J
authors.lastname: Wang
authors.forename: Arlene S
authors.initials: AS
authors.lastname: Bridges
authors.forename: Yichun
authors.initials: Y
authors.lastname: Hu
authors.forename: Susan L
authors.initials: SL
authors.lastname: Hogan
authors.forename: Reginald F
authors.initials: RF
authors.lastname: Frye
authors.forename: Joyce
authors.initials: J
authors.lastname: Blaisdell
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Goldstein
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Dooley
authors.forename: Kim L R
authors.initials: KL
authors.lastname: Brouwer
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Falk
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D002853:Chromatography, Liquid; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005921:Glomerulonephritis / Q000209:etiology / Q000503:physiopathology*; D006207:Half-Life; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000150:complications; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012709:Serum Albumin / Q000378:metabolism; D014657:Vasculitis / Q000150:complications
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012709:Serum Albumin; C012358:4-hydroxycyclophosphamide; D003520:Cyclophosphamide; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating