Physiologic Factors Related to Drug Absorption:

• Physiologic Factors Related to Drug Absorption

  The systemic absorption of a drug is dependent on (1) the physicochemical properties of the drug, (2) the nature of the drug product, and (3) the anatomy and physiology of the drug absorption site
• Proper drug product selection requires a thorough understanding of the physiologic and pathologic factors affecting drug absorption to assure therapeutic efficacy and to avoid potential drug–drug and drug–nutrient interactions
• Many drugs are not administered orally because of drug instability in the gastrointestinal tract or drug degradation by the digestive enzymes in the intestine
• Drugs not administered orally

  • erythropoietin
  • human growth hormone (somatrophin)
  • insulin
• Biotechnology products are often too labile to be administered orally and therefore are usually given parenterally
• Drug absorption after subcutaneous injection


  Slower than intravenous injection
• Pathophysiologic conditions such as burns

  Increase the permeability of drugs across the skin compared with normal intact skin
• When a drug is administered by an extravascular route of administration, the drug must first be absorbed into the systemic circulation and then diffuse or be transported to the site of action before eliciting biological and therapeutic activity
• The general principles and kinetics of absorption from these extravascular sites follow the same principles as oral dosing, although the physiology of the site of administration differs
• Radioactive isotopes


  Routinely used to trace the fate of drugs in disposition and metabolism studies conducted during drug discovery and development
• Radiolabeled studies


  • comparative in vitro metabolism
  • absorption, distribution, metabolism and elimination (ADME) studies in toxicological species
  • tissue distribution study in rats or other species
  • ADME study in humans
  • enzymatic studies to identify the enzymes involved in the metabolism of the drug, and the kinetics of the metabolic reactions
  • investigative drug metabolism studies to address issues related to drug metabolism and disposition
• All these radiolabeled studies, except for the tissue distribution study, require metabolite profiling to determine the number and relative concentrations of individual metabolites in various biological matrices using a radiochromatographic technique
• Half-life (t1/2)


  The time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%
• For the simplest case, the one-compartment model half-life may be determined readily by inspection and used to make decisions about drug dosage
• Drug concentrations in plasma often follow a multiexponential pattern of decline; two or more half-life terms thus may be calculated
• t1/2 = 0.693 * Vss / CL


  Vss = Volume of distribution at steady state, CL = Clearance
• As clearance decreases, owing to a disease process, for example, half-life would be expected to increase. However, this reciprocal relationship is valid only when the disease does not change the volume of distribution
• Changes in protein binding of a drug may affect its clearance as well as its volume of distribution, leading to unpredictable changes in half-life as a function of disease
• Steady State


  A steady-state concentration eventually will be achieved when a drug is administered at a constant rate. At this point, drug elimination [the product of clearance and concentration] is equal to the rate of drug administration
• This concept also extends to regular intermittent dosage (e.g., 250 mg of drug every 8 hours). During each interdose interval, the concentration of drug rises with absorption and falls by elimination. At steady state, the entire cycle is repeated identically in each interval
• Mean Residence Time (MRT)


  The average time for all the drug molecules to reside in the body
• Calculating MRT


  Summation of the number of molecules in each group i multiplied by the residence time, t i, for each group, divided by the total number of molecules
• The drug dose (mg) may be converted to the number of molecules by dividing the dose (mg) by 1000 and the molecular weight of the drug to obtain the number of moles of drug, and then multiplying the number of moles of drug by 6.023 x 10^23 (Avogadro's number) to obtain the number of drug molecules
• MRT


  Independent of mass, calculated as the summation of the amount of drug (mg) in each group with residence time t i, divided by the total amount of drug
• Statistical Moment Theory


  Provides a unique way to study time-related changes in macroscopic events, where a macroscopic event is considered as the overall event brought about by the constitutive elements involved
• MRT provides a fundamentally different approach than classical pharmacokinetic models, which involve the concept of dose, half-life, volume, and concentration
• Changing from a slow rate of IV injection of a fast-acting drug may result in quite different response in a subject compared to rapid injection of the same drug solution, which has been attributed to a transient change in concentration at the site or explained by modeling the MRT change of the drug at the site