WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in cancer patients have been well described. The current study was conducted to document the pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in patients with glomerulonephritis. The study was necessary due to the numerous clinical abnormalities that are present in glomerulonephritis (altered glomerular filtration rate, proteinuria, hypoalbuminaemia) which can alter the disposition of drugs. WHAT THIS STUDY ADDS• This study documents the differences in pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in glomerulonephritis vs. the cancer population. The current results demonstrate that clinical and pharmacogenetic covariates can both alter the disposition of cyclophosphamide and 4-hydroxycyclophosphamide in glomerulonephritis. AIMSCyclophosphamide, 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. METHODSGlomerulonephritis 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. RESULTSThe mean area under the plasma concentration-time curve (AUC(0,•)) data were 110 100 Ϯ 42 900 ng ml -1 h and 5388 Ϯ 2841 ng ml -1 h for cyclophosphamide and 4-hydroxycyclophosphamide, respectively.The mean metabolic ratio was 0.06 Ϯ 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 Cmax (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 Vd (P = 0.0271, 95% CI -57.5, -4.2) and decreased Cmax (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). CONCLUSIONSPharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide in patients with lupus nephritis and small...

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Study 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 non-glomerular etiologies. Design-A prospective study design Participants-Eighteen adults with CKD Setting-General Clinical Research Center at the University of North Carolina and University of PittsburghMeasurement and Main 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±34.4L/h, 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 nonglomeruler 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 non-glomerular 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 non-glomerular 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.

Purpose The role of pharmacogenomics, clinical and demographic parameters in pharmacokinetic predictions was evaluated in patients receiving mycophenolic acid (MPA). Methods A cohort study design of patients with glomerulonephritis secondary to lupus nephritis and anti-neutrophil cytoplasmic antibody (ANCA) vasculitis was employed. Forty-six patients with lupus nephritis and ANCA vasculitis who were receiving MPA were recruited from the nephrology clinic. The study assessed the relative single and combined roles of genomic, clinical, and demographic characteristics on pharmacokinetic parameters using general linear models. The study focused on polymorphisms in UGT1A7, UGT2B7, and ABCB1/MDR1; all of which have limited data available concerning MPA pharmacokinetics. All patients had pharmacokinetic assessments for MPA and glucuronide metabolites (MPAG, AcMPAG). Genotyping was performed for known variants of UGTs (UGT1A9, UGT1A7, UGT2B7), and multidrug resistance protein (ABCB1/MDR1), involved in MPA disposition. Analyses included univariate and multivariate linear modeling. Results In univariate analyses, UGT2B7 heterozygosity (coefficient 0.3508; R2=0.0873) and UGT1A7 heterozygosity (coefficient 0.3778; R2=0.0966) predicted increased apparent oral clearance of MPA. UGT1A7 heterozygosity (coefficient −0.4647; R2 0.0897) predicted lower MPA trough concentrations. In multivariate assessments, higher urinary protein excretion, lower serum creatinine, and increased weight predicted greater apparent oral clearance of MPA (p< 0.0001). White race and higher serum creatinine predicted higher MPA trough concentrations (p<0.0001). Higher exposure to MPA was predicted by decreased urinary protein excretion and increased serum creatinine. Conclusions Clinical and demographic parameters were 2–4 times more important in MPA disposition than genotypes and explained 30–40% of the pharmacokinetic parameters.

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