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991.
Joy MS La M Wang J Bridges AS Hu Y Hogan SL Frye RF Blaisdell J Goldstein JA Dooley MA Brouwer KL Falk RJ 《British journal of clinical pharmacology》2012,74(3):445-455
AIMS
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 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).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. 相似文献992.
Yan GZ Generaux CN Yoon M Goldsmith RB Tidwell RR Hall JE Olson CA Clewell HJ Brouwer KL Paine MF 《Drug metabolism and disposition》2012,40(1):6-17
Dose selection during antiparasitic drug development in animal models and humans traditionally has relied on correlations between plasma concentrations obtained at or below maximally tolerated doses that are efficacious. The objective of this study was to improve the understanding of the relationship between dose and plasma/tissue exposure of the model antiparasitic agent, pafuramidine, using a semiphysiologically based pharmacokinetic (semi-PBPK) modeling approach. Preclinical and clinical data generated during the development of pafuramidine, a prodrug of the active metabolite, furamidine, were used. A whole-body semi-PBPK model for rats was developed based on a whole-liver PBPK model using rat isolated perfused liver data. A whole-body semi-PBPK model for humans was developed on the basis of the whole-body rat model. Scaling factors were calculated using metabolic and transport clearance data generated from rat and human sandwich-cultured hepatocytes. Both whole-body models described pafuramidine and furamidine disposition in plasma and predicted furamidine tissue (liver and kidney) exposure and excretion profiles (biliary and renal). The whole-body models predicted that the intestine contributes significantly (30-40%) to presystemic furamidine formation in both rats and humans. The predicted terminal elimination half-life of furamidine in plasma was 3- to 4-fold longer than that of pafuramidine in rats (170 versus 47 h) and humans (64 versus 19 h). The dose-plasma/tissue exposure relationship for the prodrug/active metabolite pair was determined using the whole-body models. The human model proposed a dose regimen of pafuramidine (40 mg once daily) based on a predefined efficacy-safety index. A similar approach could be used to guide dose-ranging studies in humans for next-in-class compounds. 相似文献
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S. Arends A. Spoorenberg G. A. W. Bruyn P. M. Houtman M. K. Leijsma C. G. M. Kallenberg E. Brouwer E. van der Veer 《Osteoporosis international》2011,22(5):1431-1439
Summary
Osteoporosis is a well recognized complication of ankylosing spondylitis (AS). This study indicates that increased bone turnover, inflammation, and low vitamin D levels are important in the pathophysiology of AS-related osteoporosis, and that bone turnover markers (BTM) are valuable markers to detect bone loss in AS. 相似文献998.
999.
Koerts J Tucha L Leenders KL van Beilen M Brouwer WH Tucha O 《Journal of the neurological sciences》2011,310(1-2):172-175
Impairments in executive functions (EF) in Parkinson's disease (PD) will have a negative influence on daily life. For the assessment objective and subjective measurement approaches are used. It is however unknown whether these approaches contribute in a different way to the assessment of EF in PD. Thirty-nine PD patients and 24 healthy participants completed the Dysexecutive questionnaire (DEX; subjective measure) and the Frontal Assessment Battery (FAB; objective measure). PD patients showed impaired EF (FAB) and reported more problems with EF in daily life (DEX) than healthy participants. The performance on the FAB could however not be explained by the problems with EF that were reported by PD patients (DEX) and vice versa. In conclusion, not all PD patients who show impairments in EF report them and not all PD patients who report problems with EF in daily life show impairments according to objective measurement. Both measures thus contribute in a different way to the assessment of EF in PD patients. However, it has to be considered that the FAB is not a critical test to assess cognition in PD, since these patients also suffer from posterior abnormalities including memory and visuo-spatial deficits which are strong predictors for PD dementia. 相似文献
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