title: Artificial neural network modeling for drug dialyzability prediction.
abstract: OBJECTIVE
  The purpose of this study was to develop an artificial neural network (ANN) model to predict drug removal during dialysis based on drug properties and dialysis conditions. Nine antihypertensive drugs were chosen as model for this study.
  
  
  METHODS
  Drugs were dissolved in a physiologic buffer and dialysed in vitro in different dialysis conditions (UFRmin/UFRmax, with/without BSA). Samples were taken at regular intervals and frozen at -20ºC until analysis. Extraction methods were developed for drugs that were dialysed with BSA in the buffer. Drug concentrations were quantified by high performance liquid chromatography (HPLC) or mass spectrometry (LC/MS/MS). Dialysis clearances (CLDs) were calculated using the obtained drug concentrations. An ANOVA with Scheffe's pairwise adjustments was performed on the collected data in order to investigate the impact of drug plasma protein binding and ultrafiltration rate (UFR) on CLD. The software Neurosolutions was used to build ANNs that would be able to predict drug CLD (output). The inputs consisted of dialysis UFR and the herein drug properties: molecular weight (MW), logD and plasma protein binding.
  
  
  RESULTS
  Observed CLDs were very high for the majority of the drugs studied. The addition of BSA in the physiologic buffer statistically significantly decreased CLD for carvedilol (p= 0.002) and labetalol (p<0.001), but made no significant difference for atenolol (p= 0.100). In contrast, varying UFR does not significantly affect CLD (p>0.025). Multiple ANNs were built and compared, the best model was a Jordan and Elman network which showed learning stability and good predictive results (MSEtesting = 129).
  
  
  CONCLUSIONS
  In this study, we have developed an ANN-model which is able to predict drug removal during dialysis. Since experimental determination of all existing drug CLDs is not realistic, ANNs represent a promising tool for the prediction of drug CLD using drug properties and dialysis conditions.
authors.forename: Kahina
authors.initials: K
authors.lastname: Daheb
authors.forename: Mark L
authors.initials: ML
authors.lastname: Lipman
authors.forename: Patrice
authors.initials: P
authors.lastname: Hildgen
authors.forename: Julie J
authors.initials: JJ
authors.lastname: Roy
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000493:pharmacokinetics*; D000959:Antihypertensive Agents / Q000493:pharmacokinetics*; D006801:Humans; D008567:Membranes, Artificial; D016571:Neural Networks, Computer; D006435:Renal Dialysis; D012710:Serum Albumin, Bovine / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D008567:Membranes, Artificial; D012710:Serum Albumin, Bovine