DRUG BIOTRANSFORMATION Flashcards
These drugs can result in significant drug-drug interaction or DDI because of the compromise of intestinal metabolism.
Felodipine and Cyclosporine A
Felodipine acts as _______ and help and lowering high blood pressure
Calcium channel blocker
Principal organ of drug metabolism
Liver
Other organs that participate in drug metabolism
Kidneys, lungs, skin, brain
A term used for drugs that are orally administered, absorbed intact in the small intestine, and transported first via the portal system of the liver.
First-pass effect
These orally administered drugs are more extensively metabolized in the intestine than in the liver.
Clonazepam (seizure)
Chlorpromazine (psychotic disorders)
Cyclosporine (immunosuppresant)
True or False. First pass effect may limit the bioavailability of orally administered drugs such as lidocaine (anes).
True
Some of the enzymes affect drugs…Identify what enzymes affect the following:
- Penicillin
- Polypeptides such as insulin
- Sympathomimetic catecholamines
- gastric acid
- digestive enzymes
- enzymes in the wall of the intestine
Most transformations are catalyzed by specific cellular enzymes. At the subcellular level, these enzymes are located in the?
- endoplasmic reticulum
- mitochondria
- cytosol
- lysosomes
- nuclear envelope
- plasma membrane
Many drug metabolizing enzymes are located in the ________.
Lipophilic endoplasmic reticulum membranes of the liver and other tissues.
When lamellar membranes are isolated by homogenization and fractionation of cells, they reform into vesicles known as
MICROSOMES
- microsomes retain: intact membranes (rer and ser)
- smooth microsomes: responsible for oxidative drug metabolism
- smooth microsomes: contain mixed function oxidases or monooxygenases.
Reducing agents required by MFO (monooxygenases)
NADPH and molecular oxygen (Nicotinamide adenine dinucleotide phosphate)
-1 molecule of oxygen is reduced per substrate molecule (one oxygen atom appears in the product and the other in the form of water)
2 microsomal enzymes that play key role in oxidation-reduction process
- NADPH-cytochrome P450 oxidoreductase (POR or CPR)
- Cytochrome P450 (P450 or CYP)
one mole of this microsomal enzyme contains 1 mol each of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD)
-NADPH-cytochrome P450 oxidoreductase (POR or CPR)
serves as terminal oxidase; a hemoprotein; multiple forms of this is present in the microsomal membrane;
-its multiplicity is increased by repeated administration of or exposure to exogenous chemicals
Cytochrome P450 (P450 or CYP)
In the reduced form of Cytochrome P450 (P450 or CYp), it binds ________ to give complex that absorbs light maximally at 450 nm.
Carbon monoxide
Because of its relative abundance, this step has become a rate-limiting step in hepatic drug oxidations
P450 heme reduction
Microsomal drug oxidation requires? (4)
- P450
- P450 reductase
- NADPH
- Molecular Oxygen
Step 1 of cytochrome P450 cycle in drug oxidation
Oxidized (Fe+3) P450 combine with a drug substrate and form binary complex.
Step 2 of cytochrome P450 cycle in drug oxidation
NADPH donates an electron to the flavoprotein P450 reductase which in turn reduces oxidized P450-drug complex
most dominant enzymes
uridine 5′-diphosphate (UDP)-glucuronosyl transferases (UGTs)
encode UGT proteins involved in the metabolism of drugs and xenobiotics.
nineteen UGT genes (UGTA1 and UGT2)
11 human sulfotransferases (SULTs) catalyze the sulfation of substrates using_________ as the endogenous sulfate donor.
3′-phospho- adenosine 5′-phosphosulfate (PAPS)
Also engaged in the metabolism of drugs and xenobiotics, and in that of leukotrienes and prostaglandins, respectively.
Cytosolic and microsomal glutathione (GSH) transferases (GSTs)
