Drug Biotransformation-DSA-Kruse Flashcards
Give a classical example of a drug that undergoes extensive first-pass biotransformation:
Morphine
Xenobiotic metabolizing enzymes have historically been grouped into __ rxns in which enzymes carry out oxidation, reduction, or hydrolytic rxns
Phase 1
__ rxns involve enzymes that form a conjugate of the substrate
Phase 2
As a general rule, __ rxns result in the biological inactivation of the drug while ___ rxns produce a metabolite with improved water solubulity and increased MW which facilitates the elimination of the drug from the body
Phase 1
Phase 2
List characteristics of Phase 1 rxns:
- Catabolic
- enzymes that convert parent drug to more polar metabolite
- oxidation, reduction, hydrolyssis rxns
- carried out by mixed function oxidases (MFOs) or monoxygenases
- Cyt P 450 are primary phase 1 enzymes
- Phase 1 products generally more reactive and may be more toxic than parent drug
- Phase 1 enzymes are located in lipophilic ER membranes of the liver
List characteristics of phase 2 rxns
- anabolic
- enzymes that form a conjugate of the substrate (phase 1 product)
- drug conjugates are polar molecules with higher MW that are readily excreted and often inactive compared to their precursors
- conjugation is dependent upon endogenous substrates such as glucuronic acid, sulfuric acid, acetic acid or an amino acid
- conjugation occurs at significantly faster rates than phase 1 rxns
- most conjugation takes place in the liver
___ is the most abundantly expressed CYP450 enzyme and involved in the metabolism of about 50% of clinically used drugs
CYP3A4
P450s used molecular O2 and H+ derived from __ cofactor to carry out oxidation of substrates
NADPH
An individual with a genetic defect in pseudocholinesterase will metabolize the depolarizing neuromuscular blocking drug, succinylcholine, at what rate compared to normal individuals?
Metabolize succinylcholine at 50% the rate as normal individuals
Describe the effects of an individual who is a slow acetylator due to an autosomal recessive trait with a decrease in N-acetyltransferase levels:
Isoniazid (treat TB), hydralazine (treat HTN), caffeine, are metabolized at SLOWER rates which can lead to hepatotoxicity (hepatitis)
-phenotype occurs in roughly 50% US pop., 83% of french pop., and less common in asian pops.
List some well-characterized enzyme inducers:
Phenytoin (anticonvulsant), chronic ethanol (CYP2E1), aromatic hydrocarbons such as benzo[a]pyrene (tobacco smoke), rifampin (anti TB), phenobarbital other barbiturates (historically used for sedation and anesthesia induction)
In irreversible inhibition, what type of bond is present?
Covalent bond
-interaction between drug/compound and enzyme is covalent in the case of irreversible inhibition and leaves the enzyme permanently inhibited
Consumption of grapefruit juice with drugs taken orally can irreversibly inhibit intestinal ___
CYP3A4
-the inhibition alters the oral bioavailability of many classes of drugs, including antihypertensives, immunosuppressants, antidepressants, antihistamines, and statins
What happens with coadministration of allopurinol with mercaptopurine?
Coadministration of allopurinol with mercaptopurine prolongs the duration of mercaptopurine action and enhances its chemotherapeutic and toxic effects
-Doses of mercaptopurine must be reduced in pts receiving allopurinol
For drugs whose biotransformation is flow-limited, cardiac disease may cause specific drug levels to ___
Rise
-e.g., drugs such as alprenolol and propanolol (beta blockers), isoniazid (anti TB), lidocaine (local anesthetic), morphine, and verapamil (Ca channel blocker)
