BIOTRANSFORMATION AND METABOLISM

• BIOTRANSFORMATION: Drugs being metabolized by enzymes and chemical reactions in the body before they are eliminated.• Altered drug is known as a METABOLITE. It is usually hydrophilic and eliminated by the

kidneys or liver.• The majority of these enzymes are found in the liver.

• Phase 1 of Biotransformation:• Original drug molecule is chemically transformed. Common changes include adding or

removing oxygen, hydrogen, etc.• The metabolite is now typically less biologically active.

• Phase 2 of Biotransformation:• The metabolite is conjugated, or joined with another molecule to make it more

hydrophilic and able to be excreted in the urine.

DRUG INTERACTIONS AFFECTING BIOTRANSFORMATION

• Multiple drugs in the body at the same time can interact with one another and effect each other’s biotransformation.

• The MFO (mixed function oxidase) system is one of the most common biotransformation enzyme systems in the liver.

• Exposure to certain drugs can increase the number of enzymes in this system with each repeated exposure. These drugs end up being metabolized at an increased rate. This is referred to as INDUCED METABOLISM.

• Induced metabolism shortens the amount of time that the drug can be effective in the body (also known as TOLERANCE).

SPECIES AND AGE DIFFERENCES IN DRUG BIOTRANSFORMATION

• Just because a drug is safe to use in one species, does not mean it is safe to use in all species.

• The liver needs time after birth to finish developing (approx. 5 weeks).

• Since the liver is a major route of biotransformation, caution should be used when administering any drug to neonates that requires the liver to metabolize it.

• Older animals may have a decline in liver and/or kidney function, as is common in geriatric animals. Dosages should be adjusted or alternative medications used if these organs biotransform the medications.

DRUG ELIMINATION

• ELIMINATION: also known as excretion, the movement of drug molecules out of the body

• Routes of elimination: feces, urine, sweat, exhalation, milk, saliva, keratin• *Major routes of elimination are into the urine (kidneys), and the feces (bile from the

liver).

• Changes in elimination can occur with dehydration, degeneration of kidneys or liver with age or diseases that affect those organs.• Dosages must be adjusted to avoid toxicity

RENAL ELIMINATION

• Two ways that drugs are eliminated via the kidney: filtration at the glomerulus and active secretion in the tubules

• Filtration is passive and occurs as blood flows through the glomerulus into Bowman’s Capsule.

• Proteins are too large to be filtered, so drugs that are protein bound will remain in the bloodstream at this point. Drugs that are not protein-bound should be able to be filtered.

RENAL ELIMINATION

• Two ways that drugs are eliminated via the kidney: filtration at the glomerulus and active secretion in the tubules.

• Secretion can occur as early as the proximal convoluted tubule. Secretion involves drug molecules being actively transported from the peritubular capillaries into the urine. No concentration gradient is necessary.

• Protein-bound drugs can detach from its protein and bond to a transport molecule in the cell membrane of the tubule and the drug can be secreted in the urine. If it stays attached to the protein, it will remain in the blood.

• Once in the tubular filtrate, drug molecules that are lipophilic can be reabsorbed back into the bloodstream as it travels to the Loop of Henle.

• After the Loop of Henle, drug concentrations in the urine seldom change.

HEPATIC ELIMINATION

•Blood from the GI tract and the rest of the body flows through the liver. Drugs excreted by the liver diffuse into hepatocytes and then enter the bile (changed or unchanged).

•Bile is collected in the gallbladder and then dumped into the duodenum.

•Lipophilic drug molecules have the opportunity to be reabsorbed in the small intestines and make a second trip to the liver and repeat the cycle. This is known as ENTEROHEPATIC CIRCULATION. Drugs in this circulation can effect the body for a longer duration of time than those that don‘t reenter the circulation.

•Like the kidneys, drug dosages must be reduced when giving drugs eliminated via billiary excretion to patients with liver Insufficiency.

HALF-LIFE AND CLEARANCE

• HALF-LIFE OF ELIMINATION/CLEARANCE: the rate at which drugs leave the body.

• Measure of how fast a volume of blood is cleared of the drug• Expressed as a volume of blood cleared over time • Time value that describes how long the drug concentration takes to decrease by

50%• Typically decreases over time in a curve• May dictate how frequently the drug must be given to maintain concentrations in

therapeutic range • May reflect how well the organs that eliminate the drug are functioning

RELATION OF HALF-LIFE TO STEADY-STATE

CONCENTRATIONS

• STEADY-STATE: a point at which drug levels plateau and all peak concentrations are the same and all trough concentrations are the same

• Happens when a drug is given repeatedly • The amount of drug being administered equals the amount of drug being eliminated • After the time of one half life has passed, the peak and trough concentrations are 50%

of what they will be when they achieve steady-state •The time from beginning of therapy to steady state is approximately five times the half life

•Example: a drug with a half life of 6 hours will take 30 hours to reach steady state

DRUG WITHDRAWAL TIMES

• WITHDRAWAL TIME: the time (in days) after a drug is administered during which the animal cannot be sent to slaughter and the eggs/milk must be discarded

• Drug residues in food is a growing concern for people

• All drugs approved for use in food animals have a withdrawal time

• Drug must not only be out of the bloodstream, but also all of the tissues

• Waiting period can result in loss of money to the food animal producer, but there are severe fines/penalties for not following withdrawal times.