Druglikeness and biopharmaceutics

• Why must a drug go into solution?

  To be absorbed and act on its target
• What is the balance required for drug effectiveness?

  Hydrophilicity and lipophilicity
• What is Lipinski's Rule of Five related to?

  Druglikeness and absorption
• What is the maximum number of hydrogen bond donors according to the Rule of 5?

  Less than 5
• What is the maximum molecular weight according to the Rule of 5?

  Less than 500 Da
• What is the maximum LogP value according to the Rule of 5?

  Less than 5
• How many parameters must a drug obey for oral absorption?

  Two or more parameters
• What are the limitations of the Rule of 5?

  • Accounts for solubility but not dissolution
  • Does not account for transporter absorption
  • Accounts for low but not high aqueous solubility
• What is the lower limit for polar surface area according to the additions to improve predictive power?

  Less than 14 nm²
• What is the combined hydrogen bond donor and acceptor limit?

  Less than 12
• What are the BCS drug classes based on solubility and permeability?

  • Class I: High solubility, high permeability
  • Class II: Low solubility, high permeability
  • Class III: High solubility, low permeability
  • Class IV: Low solubility, low permeability
• What does BCS Class I indicate about a drug?

  High solubility and high permeability
• What does BCS Class II indicate about a drug?

  Low solubility but high permeability
• What does BCS Class III indicate about a drug?

  High solubility but low permeability
• What does BCS Class IV indicate about a drug?

  Low solubility and low permeability
• What is the definition of high solubility in BCS?

  • Highest dose dissolves in < 250 mL of water
  • pH range of 1-7.5 at 37ºC
• How is solubility considered in BCS?

  By taking into account the dose
• What is the solubility of aspirin?

  4.6 mg/mL
• Why is aspirin considered high solubility?

  300 mg/250 mL equals 1.2 mg/mL
• What is the solubility of ibuprofen?

  0.021 mg/mL
• Why is ibuprofen considered low solubility?

  600 mg/250 mL equals 2.4 mg/mL
• What are the two ways to determine permeability in BCS?

  1. Bioavailability testing in humans
  2. In vitro permeability testing
• What defines high permeability according to the FDA?

  Absorption greater than or equal to 90%
• What is bioavailability (F)?

  • Measure of fraction of drug absorbed
  • Ratio of drug absorbed orally to IV
• How is bioavailability calculated?

  Using AUC and doses for oral and IV
• What does an F value of 1 indicate?

  All drug is absorbed orally
• What does an F value of 0.5 indicate?

  Half the drug is absorbed orally
• What is the formula for permeability in vitro?

  $J =$$P(C)$

  • J: rate of flux (g/cm²/s)
  • P: permeability coefficient (cm/s)
• What is the purpose of in vitro intestinal cell cultures?

  To determine permeability and predict absorption
• What is the method of administration for the drug mentioned?

  Administered via IV bolus
• What does BCS stand for in pharmacology?

  • Biopharmaceutics Classification System
• How is the F value calculated?

  F = AUC_ORAL ÷ DOSE_ORAL ÷ AUC_IV ÷ DOSE_IV
• What is the formula for calculating permeability in vitro?

  • J = P(C)
  • J: rate of flux (g/cm²/s)
  • P: Permeability coefficient (cm/s)
  • C: concentration at the membrane surface
• What does the apparent permeability coefficient (P_APP) indicate?

  It estimates permeability and absorption fraction
• What is the P_APP value predictive of high permeability?

  P_APP > 1 × 10^-5 cm/s
• What is LogP used for in drug permeability?

  It substitutes P_APP for permeability estimation
• What LogP value indicates good permeability?

  LogP > 2 and < 5
• What is the BCS class for caffeine?

  BCS Class I
• What is the BCS class for aspirin?

  BCS Class III
• What is the BCS class for diazepam?

  BCS Class I