Biotransformation & Drug Response Modifiers
Any compound that enters the body must either be incorporated into the normal function of the body or be eliminated.
The most common way of eliminating a substance is through renal excretion.
Compounds to be excreted must have a good deal of water solubility. If a compound is not sufficiently water soluble the body must change it in some way to increase its water solubility. When the body acts to change the chemical structure of a substance it is known as biotransformantion.
Biotransformation is very complex.
It is structurally specific
It is emzyme meatiated
It requires energy
It is unidirectional
Phase I vs Phase II biotransformation
Phase I Introduce a functional group
Include oxidation, reduction, or hydrolysis
Cytochromes P450 or heme-thiolate P450 are a family of enzymes that act on substances to convert them
from a lipid to an aqueous soluble material
See Figure 13-1
Substrates for each enzyme in the family have similar structural requirements. Thus we can sometime predict the potential metabolic fate of a compound based on the structural similarities to compounds whose metabolism is well known.
Tables 13-1,2,3,&4 Show example substrates for four different members of the P450 family of enzymes.
Please note the similarities in the substrate functional groups and electronic status of the compounds at physiological state.
Individual variability in response to drugs can sometimes be traced to individual variation in the % of the Cytochromes of each type. See figure 13-2.
You can see that changes in the amount of CYP2E1 could dramatically increase or decrease the rate of metabolism of ethanol.
We can now phenotype people and use that information to help predict or at least explain drug sensitivity (either increased or decreased effectiveness)
Some drugs alter the effectiveness of the enzymes in the body and can affect the metabolism and subsequent clearance of other drugs. Both enzyme induction and enzyme inhibition can occur.
Please review carefully table 13-5 on page 145.
Phase II Conjugation
Add a functional group or compound which increase water solubility
Glucuronidation or Sulfate are the most common
Can be responsible for age dependent difference in pharmacokinetics of some drugs.
Specific Factors that Influence Drug Metabolism
Stereoselectivity
Chronopharmacokinetics
First Pass
dC/dt = - Vmax
iC
Km + C
This equation is very important. You will see it over and over again. Get to understand it as soon as possible!!!
Chapter 30 on pages 377 to 385
Body Weight
Age Newborn, Children, Aged(>65)
Sex
Body Temperature
Gastric Emptying
Blood Flow Rates
Environment
Nutrition
Pregnancy
Genetics
Circadian Rhythm
Cardiovascular Diseases
Renal Diseases
Liver Diseases
SEE TABLE 30-1 on page 383