Lesson 2 Flashcards
What is a xenobiotic?
chemical substance found within an organism that is not naturally produced or expected to be present within the organism
How are xenobiotic transported in the blood? Which characteristic allow a better transport?
Thanks to plasma protein, expecially albumin. Blood cells can trasport in few cases. They work weel expecially for lipophilic drug because they can be extensively bound.
Main characteristics of albumin?
- plasma protein
- regulate oncotic pressure
- bind weak acids
- bind xenobiotics and endogenous compounds
Which are the plasma proteins (other than albumin) that may transport xenobiotics?
α1-acid glycoprotein: bind basic drugs and cause relaxation of the vessel’s muscle during inflamation
lipoproteins: bind lipophilic compound in an unspecific way
Globulins: bind trace elements such as Fe and Cu
How is the binding between drug and albumin? Which drugs can be specifically bound?
The majority of drugs bind to albumins in an unspecific way, there are very few specific binding sites (walfarin, benzodiazepines and digitoxin in humans).
Describe the structure of the BBB. Which compound can cross it?
The BBB Is formed by endothelial cells connected by tight junctions (capillaries) and astrocytes (glial cells) that adhere to the endothelial cells.
Only very lipophilic compound may cross the BBB.
Which factors may affect the BBB functioning?
- Age: in toddler it isn’t fully developed
- Genetic polymorphism: mutation may cause poorly functioning transporters (ex:PGP in dogs) which may increase the sensitivity to drugs
- Inflammation: make BBB more permeable, some antibiotics benefit of this situation because thay can penetrate more easily
Divide the tissues of the organism according to their transfer rate of drug distribution
- Rapid: CNS, heart, kidney, liver, lung. Flow: 20-400 ml/min/100g
- Intermediate: muscle, skin. Flow: 1-20 ml/min/100g
- Slow: teeth, ligaments, fat, bones. Flow: 1ml/min/100g
Which are the sites of accumulation of xenobiotics?
- Fat: lipophilic substances
- Liver and kidney: trace elements (steroids, bilirubin, metals) bound to ligandins
What is the re-distribution?
A part of lipophilic drugs are sequesterd by fat and stored in adipose tissue. When the organism require energy, the lipolytic process in fat is activated and the lipophilic substances are released in the blood stream.
Which is the role of the biotransformation enzymes?
The modify the physio-chemical properties of substrates, transforming them in more polar or less lipophilic structures (accettable for excretion)
How many substances can be bound by the xenobiotic metabolizing enzymes ?
These enzymes have a low substrate specificity so they can accomodate a wide range of substrates with widely different chemical structure.
What is Km? Which are its consequences?
Km is the concentration required to reach half of the maximum velocity (Vmax) of the reaction.
Lower the concentration, higher the affinity, higher the rate of reaction
Which are the two phases of the biotransformation? Which kind of reaction occurs and where?
Phase 1: oxidation, reduction, hydrolitic reaction.Polar groups (OH, COOH, NH2) are introduced or unmasked and the parent compound is transformed in polar metabolites.
Enzymes are in the smooth ER and in the mitochondria
Phase 2: several chemical groups (from glucuronic acid, acetic acid, sulfate…) are conjugated in order to form conjugated metabolites than can be excreted by urine. Enzymes are in the cytosol, exept for UGT
How biotransformation affect drug persistance?
the higher level of biotransformation lead to the lower drug persistence. In most cases drug effect is limited to the parent compound
