Computational modeling in_drug_disposition[1]

Computational modeling in_drug_disposition[1]

• 1.
  COMPUTATIONAL MODELING IN DRUGDISPOSITION Presented by : Nikita Gidde. M. Pharm, Sem-II. Department of Pharmaceutics. Rajarambapu College of pharmacy, Kasegaon. 1
• 2.
  CONTENTS 1. Introduction 2. ModelingTechnique 3. Drug Absorption 4. Drug Distribution 5. Drug Excretion 2
• 3.
  INTRODUCTION  Efficacy andselectivity against the biological target.  Half of drug candidates fail at phase II and phase III clinical trials because of the undesirable drug pharmacokinetics properties  To reduce the attrition rate at more expensive later stages, in vitro evaluation of ADMET properties in the early phase of drug discovery has widely adopted. 3
• 4.
  MODELING TECHNIQUE Consist 2Approaches: 1.Quantitative approaches Quantitative approaches represented by pharmacophore modeling and flexible docking studies Useful when there is an accumulation of knowledge against certain target. Three widely used automated pharmacophore perception tools are DISCO (DIStance COmparisons), GASP (Genetic Algorithm Similarity Program) and Catalyst 4
• 5.
  MODELING TECHNIQUE CONT…. 2.Qualitativeapproaches The qualitative approaches represented by quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) studies It is essential to select the right mathematical tool for most effective ADMET modeling. 5
• 6.
  DRUG DISPOSITION Drug Disposition Absorption Solubility Intestinal Permeability Active Transport Distribution Volume of Distribution plasma- protein binding(PPB) blood-brain barrier (BBB) permeability Excretion Renal Hepatic 6
• 7.
  DRUG ABSORPTION  Becauseof its convenience and good patient compliance, oral administration is the most preferred drug delivery form.  In general, drug bioavailability and absorption is the result of the interplay between drug solubility and intestinal permeability. 7
• 8.
  DRUG DISTRIBUTION  Distributionis an important aspect of drug’s pharmacokinetic profile.  The structural and physiochemical properties of a drug determine the extent of distribution, which is mainly reflected by three parameters: 1. volume of distribution (Vd), 2. plasma-protein binding (PPB) and 3. blood-brain barrier (BBB) permeability. 8
• 9.
  DRUG EXCRETION  Theexcretion or clearance of a drug is quantified by plasma clearance, which is defined as plasma volume that has been cleared completely free of drug per unit of time.  Together with Vd, it can assist in the calculation of drug half-life, thus determining the dosage regimen.  Hepatic and renal clearances are the two main components of plasma clearance.  Current modeling efforts are mainly focused on estimating in vivo clearance from in vitro data.  Just like other pharmacokinetic aspects, the hepatic and renal clearance process is also complicated by presence of active transporters. 9
• 10.
  REFERENCES  Ekins S,“Computer Applications in Pharmaceutical Research and Development”, (2006) John Wiley and Sons Inc., chapter 20, pp495-508  Ekins S, Nikolsky Y and Nikolskaya T. Techniques: Application of systems biology to absorption, distribution, metabolism, excretion and toxicity. Trends Pharmacol Sci 2005;26;202-9 10
• 11.
  11