Hepatic Drug Elimination Flashcards
What are the 2 methods how drugs can be eliminated?
Renal and hepatic clearance assumed they are independent and additive
Describe drugs that are eliminated highly by hepatic metabolism?
Are dependent on the intrinsic ability of metab0lizing enzymes displaying large inter-individual variability due to generic and environmental factors
Describe drugs that are eliminated primarily by renal excretion unchanged?
Are highly dependent on the glomerular filtration rate (GFR) and blood flow to the kidney -> which display less inter-individual variability
GFR is relatively constant among individuals with normal renal function
What is clinically useful information for determining drug elimination?
The percentage of drug excreted as unchanged and the percent of drug metabolized
What happens if the renal excretion pathway becomes impaired?
Less drug will be excreted because lipophilic drugs can not be metabolized for excretion therefore drug will accumulate in the body. Increasing toxicity
How do you calculate k for excretion
What is ke?
Elimination rate constant due to excretion
For drugs that is easily obtained wither from drug literature in the form of fraction of dose excreted unchanged or urine data
How do you calculate fraction of dose excreted in urine?
What happens if hepatic excretion pathway is impaired?
More drug will be excreted unchanged
What is km?
Elimination rate constant due to metabolism
Km = kmA + Kmart + kmC + etc
What are the approaches to obtain km?
- Drug literature in the form of fraction of drug dose metabolized
- The difference between k and ke
How do you calculate km by fraction of drug metabolized?
Describe the relationship between fm and fe?
fm can indirectly be obtained if fe (fraction of drug excreted unchanged)
fm = 1-fe
How can km be determined by k and ke?
What is extrahepatic metabolism and name an example of a drug that undergoes it?
Nitroglycerin is metabolized extensively outside the live
How do you assess extrahepatic metabolism?
Calculate hepatic (metabolic) and renal clearance of the drug and compare these clearances to total body clearance
What order is the drug metabolism and excretion assumed to be?
First order
What are most drugs 1st order metabolic and elimination kinetics?
- Concentration of drug metabolizing enzymes in the body is constant
- Therapeutic (target) drug concentrations in plasma are much lower and don’t saturate the enzymes that are involved in the metabolism for most drugs
- Most drugs are presented to metabolizing enzymes as concentrations well below the enzymes maximal capacity
- Availability of enzymes is not an issu
- Rate of drug metabolism will only depend on the concentration of the drug
- Drug elimination by metabolism for most drugs is 1st order
Describe the enzyme kinetics if there is a higher drug concentration?
Metabolizing enzymes have limited capacity, they saturate resulting in drug elimination by metabolism occurs at a constant maximal rate (zero order_
What is non-linear Michaelis -Menten kinetic equation?
Describe the rate of drug elimination by metabolism depends on both drug concentration and the concentration of drug metabolizing enzymes
The hyperbolic (nonlinear) relationship between enzymatic reaction velocity and drug concentration
What does enzyme kinetics consider?
1 mole of drug interacts with 1 mole of an enzyme to form enzyme-drug intermediate which further decomposes to product (metabolite)
What does MM equation assume?
The rate of an enzyme reaction is dependent on the concentrations of both the enzyme and the drug
Describe the kinetics when drug concentration is low compared to the enzyme concentration?
There is an abundance of enzymes to catalyze the reaction the rate of metabolism is 1st order
Describe the kinetics when drug concentration is plasma is higher than enzyme concentration?
All enzymes become occupied with drug, the rate of metabolism is maximum, the rate process becomes 0 order
