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Clearance Pathways (clearance + pathway)

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Medical Sciences100%

Selected Abstracts

Pharmacokinetics, bioavailability and effects on electrocardiographic parameters of oral fludarabine phosphate

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 1 2010
Wei Yin
Abstract The pharmacokinetics, bioavailability and effects on electrocardiographic (ECG) parameters of fludarabine phosphate (2F-ara-AMP) were evaluated in adult patients with B-cell chronic lymphocytic leukemia. Patients received single doses of intravenous (IV) (25,mg/m2, n=14) or oral (40,mg/m2, n=42) 2F-ara-AMP. Plasma concentrations of drug and metabolites and digital 12-lead ECGs were monitored for 23,h after dosing. The dephosphorylated product fludarabine (2F-ara-A) was the principal metabolite present in the systemic circulation. Mean (±SD) elimination half-life did not differ significantly between IV and oral dosage groups (11.3±4.0 vs 9.7±2.0,h, p=0.053). Renal excretion was a major clearance pathway, along with transformation to a hypoxanthine metabolite 2F-ara-Hx. Estimated mean oral bioavailability of 2F-ara-A was 58%. Compared to the time-matched drug-free baseline Fridericia correction of the QT interval (QTcF), the mean QTcF change following 2F-ara-AMP did not differ from zero, and a treatment effect of >+10 and >+15 ms could be excluded following oral and IV 2F-ara-AMP, respectively. Similarly, heart rate, PR interval and QRS duration did not change following 2F-ara-AMP treatment. Thus the 25,mg/m2 IV and 40,mg/m2 oral doses of 2F-ara-AMP produce similar systemic exposure, and do not prolong QTcF, indicating low risk of drug induced Torsades de Pointes. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Clonidine disposition in children: a population analysis

PEDIATRIC ANESTHESIA, Issue 6 2007
AL Potts
Background:, There are few data describing clonidine population pharmacokinetics in children (0,15 years) despite common use. Current paediatric data, described in terms of elimination half-life or Cmax and Tmax, poorly explain variability in drug responses among individuals representative of those in whom the drug will be used clinically. Methods:, Published data from four studies investigating clonidine PK after intravenous, rectal and epidural administration (n = 42) were combined with an open-label study undertaken to examine the pharmacokinetics of IV clonidine 1,2 ,g·kg,1 bolus in children after cardiac surgery (n = 30, EC approval granted). A population pharmacokinetic analysis of clonidine time-concentration profiles (380 observations) was undertaken using nonlinear mixed effects modelling. Estimates were standardised to a 70 kg adult using allometric size models. Results:, Children had a mean age of four (SD 3.6 years, range 1 week,14 years) year and weight 17.8 (SD 12.6, range 2.8,60 kg). A two compartment disposition model with first order elimination was superior to a one compartment model. Population parameter estimates (between subject variability) were clearance (CL) 14 (CV 28.3%) 1 h,1·70 kg,1, central volume of distribution (V1) 56.7 (67.5%) l·70 kg,1, inter-compartment clearance (Q) 143 (19.1%) l h,1 70 kg,1 and peripheral volume of distribution (V2) 123 (72.8%) l.70kg,1. Clearance at birth was 4.7 l·h,1·70kg,1 and matured with a half-time of 25.5 weeks to reach 85% adult rate by 1 year of age. The volumes of distribution, but not clearance, were increased after cardiac surgery (V1 180%, V2 117%). There was a lag time of 2.6 (CV 64%) min before absorption began in the rectum. The absorption half-life from the epidural space was slower than that from the rectum 1.04 (CV31%) h vs 0.28 (CV24%) h. The relative bioavailability of epidural and rectal clonidine was unity (F = 1). Conclusions:, Clearance in neonates is approximately one third that described in adults, consistent with immature clearance pathways. Maintenance dosing, which is a function of clearance, should be reduced in neonates and infants when using a target concentration approach. [source]

SYMPOSIUM: Clearance of A, from the Brain in Alzheimer's Disease: A,-Degrading Enzymes in Alzheimer's Disease

BRAIN PATHOLOGY, Issue 2 2008
James Scott Miners
Abstract In Alzheimer's disease (AD) A, accumulates because of imbalance between the production of A, and its removal from the brain. There is increasing evidence that in most sporadic forms of AD, the accumulation of A, is partly, if not in some cases solely, because of defects in its removal,mediated through a combination of diffusion along perivascular extracellular matrix, transport across vessel walls into the blood stream and enzymatic degradation. Multiple enzymes within the central nervous system (CNS) are capable of degrading A,. Most are produced by neurons or glia, but some are expressed in the cerebral vasculature, where reduced A,-degrading activity may contribute to the development of cerebral amyloid angiopathy (CAA). Neprilysin and insulin-degrading enzyme (IDE), which have been most extensively studied, are expressed both neuronally and within the vasculature. The levels of both of these enzymes are reduced in AD although the correlation with enzyme activity is still not entirely clear. Other enzymes shown capable of degrading A,in vitro or in animal studies include plasmin; endothelin-converting enzymes ECE-1 and -2; matrix metalloproteinases MMP-2, -3 and -9; and angiotensin-converting enzyme (ACE). The levels of plasmin and plasminogen activators (uPA and tPA) and ECE-2 are reported to be reduced in AD. Reductions in neprilysin, IDE and plasmin in AD have been associated with possession of APOE,4. We found no change in the level or activity of MMP-2, -3 or -9 in AD. The level and activity of ACE are increased, the level being directly related to A, plaque load. Up-regulation of some A,-degrading enzymes may initially compensate for declining activity of others, but as age, genetic factors and diseases such as hypertension and diabetes diminish the effectiveness of other A,-clearance pathways, reductions in the activity of particular A,-degrading enzymes may become critical, leading to the development of AD and CAA. [source]

Association of FcGRIIa with Graves' disease: a potential role for dysregulated autoantibody clearance in disease onset/progression

CLINICAL ENDOCRINOLOGY, Issue 1 2010
Kadija Yesmin
Summary Objective, Although autoantibody production is a key feature of autoimmunity, it is not known whether variation in autoantibody production and clearance pathways is involved in disease susceptibility. The Fc Gamma Receptor IIa (FcGRIIa) molecule is involved in the clearance of autoantibodies and a functional single nucleotide polymorphism (SNP), rs1801274, which has been shown to alter autoantibody clearance, has been associated with a number of autoimmune diseases (AIDs) including systemic lupus erythematosus and type 1 diabetes. This study aimed to determine whether FcGRIIa is associated with Graves' disease (GD) in the UK Caucasian population by Tag SNP screening common polymorphisms within the FcGRIIa region. Design, A case control association study investigating nine Tag SNPs within FcGRIIa, which captured the majority of known common variation within this gene region. Patients, A dataset comprising 2504 UK Caucasian GD patients and 2784 geographically matched controls taken from the 1958 British Birth cohort. Measurements, We used the ,2 -test to investigate association between the Tag SNPs and GD. Results, Association between the rs1801274 (P,= 0·003, OR = 1·12 [95% CI = 1·03,1·22] and rs6427598 (P = 0·012, OR = 0·90 [95% CI = 0·83-0·98]) SNPs and GD was observed. No other SNPs showed association with GD. No associations were seen between any of the SNPs investigated and specific GD clinical phenotypes. Conclusions, This study suggests that variation in FcGRIIa predisposes to GD and further supports the role of FcGRIIa as a susceptibility locus for AIDs in general. [source]