VL 4: Pharmacokinetic process

• Fraction of administered drug that reaches the systemic circulation unchanged

• Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration

  
  

• comparing plasma levels of a drug after oral administration with plasma drug levels after IV injection

• Bioavailability of a drug administered orally is the ratio of the area calculated for oral administration compared with the area calculated for IV injection if doses are equivalent

  
  

• First-pass metabolism

  • drug enters portal circulation before systemic circulation

• Chemical instability

  • unstable in pH

• Solubility of the drug

  • very hydrophillic drugs are poorly absorbed

• Nature of the drug formulation

  • particle size, salt, form, enteric coatings nano-formulations and the presence of excipients

Compare the oral drug to a similar IV drug

• Fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma

• Plasma compartment: Approx. 6% of the body weight

• Extracellular fluid (plasma + interstitial fluid): Approx. 20% of the body weight

• Total body water (plasma + interstitial fluid + intracellular fluid): Approx. 60-70% of the body weight

• Depending on its properties, a drug can distribute into one or more of the three water compartments or become sequestered in specific tissues or cellular sites

  -> Vd will be very high, because drug is distributed over tissue as well; Drug will not be easily eliminated from the body

  -> some drugs can havt t1/2 of months

• Gives estimates of the amount of drug cleared from the body per unit time (ml/s or ml/min)

• Drug half-life (t1/2) is used to measure clearance

• Example: CL = 0.693 . Vd/t1/2

• CLtotal = CL hepatic + CL renal + Cl other

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• continuous-infusion

• multiple IV injection

  • two units once a day

  • one unit twice a day (less toxic)

• multiple oral administration

  • repeated fixed dose

  • single fixed dose

• A loading dose of drug can be injected as a single or multiple dose(s) to achieve the desired plasma level rapidly, followed by an infusion to maintain the steady state (maintenance dose)

Loading dose =(Vd)(desired steady-state plasm concentration)/F

• A loading dose is most useful for drugs that are eliminated from the body relatively slowly (longer t1/2) when the therapeutic benefit of the drug is required immediately and steady-state level need to be reached in shorter time

Disadvantages:

• The use of loading doses leads to increased risk of drug toxicity and a longer time for the concentration of the drug to fall if excess drug level occurs

• Doses administered to maintain a steady-state concentration within the therapeutic window

• It takes four to five half-lives of a drug to achieve steady-state systemic concentrations

• The dosing rate can be determined by knowing the target concentration in plasma (Cp ), clearance (CL) of the drug from the systemic circulation, and the fraction (F) absorbed (bioavailability)