Drug Disposition and Metabolism Flashcards
Describe the importance of metabolism from a drug therapy perspective
Aids in elimination of drugs from the body (increased clearance, decreased plasma half life for many drugs)
Acts to limit absorption of orally administered drugs
What are the basic principles of drug metabolism?
Metabolism often removes biological activity, but can also result in active drug
Most metabolism follows first-order kinetics; rate of loss is proportional to concentration in plasma
First order enzyme kinetics takes approximately 5 half lives to essentially remove the drug from the body (however some drugs can be stored in fat cells for a longer period of time)
What is the first pass effect?
Oral drugs are absorbed through the duodenum, and travel through the hepatic portal vein to the liver, where metabolism begins before the drug makes it to the bloodstream
What are the key points of drug metabolism?
Most drugs are metabolized before being eliminated from the body
Drug metabolites are usually more polar than their parent compound
The expression of drug metabolizing enzymes differs among tissue type
Ingestion of 2 or more drugs can affect the rate of metabolism in one or both drugs
How are the drug metabolism reactions divided?
Phase 1 reactions - drug is modified (oxidation, reduction, hydrolysis)
Phase 2 reactions - drug is inactivated (glucurondiation, sulfation, acetylation)
What are the stages of drug transformation
Absorption, Metabolism (phase I, phase II) and elimination
What is the order of the phases?
There is more than one path: Phase I then phase II Just phase I Just phase II Neither phase Phase I, then phase II then phase I again
What are example of phase II reactions?
Glucuronidation (carboxylic acid, alcohol, phenol, amine)
Amino acids (carboxylic acids)
Acetylation (amines)
Sulfation (alcohol, phenol, amine)
Glutathione conjugation (halo-cpds, epoxides, arene oxides, quinone-imine)
What are the therapeutic consequences of phase I and phase II metabolism?
Accelerated renal excretion Drug inactivation (particularly phase I) Activation of prodrugs Decreased toxicity Increased therapeutic action Increased toxicity
What are the hepatic drug metabolizing enzymes?
Drug metabolism is performed by microsomal enzyme system aka P450 system
Describe the P450 system
It consists of 12 families
3 of these families metabolize drugs (CYP 1, 2, 3)
9 of these families metabolize steroids and fatty acids, etc.
What is the most important drug metabolizing enzyme?
CYP3A4
CYP3A5
What are the four essential constituents for P450 drug oxidation?
NADPH
Molecular oxygen
P450 reductase (flavoprotein)
P450 enzyme (heme protein)
What are examples of CYP3A4 substrates?
Acetaminophen
Cocaine
Testosterone
What are examples of CYP3A4 inducers? What can inducers do?
St. John’s Wort
Inducers can induce expression of CYP3A4, which can increase the rate of metabolism of CYP3A4 substrates, leading to a decrease in effect
What are examples of CYP3A4 inhibitors? What can inhibitors do?
Grapefruit juice
Inhibitors inhibit the expression of CYP3A4, which can decrease the rate of metabolism CYP3A4 substrates, leading to an increase in effect
How do enzymes induce the expression CYP enzymes
The mechanism involves the binding of the drug to a site on the gene encoding the enzyme. This increases the synthesis of the enzyme
What are examples of enzyme induction?
Phenytoin is an anticonvulsant medication, which over time causes an increase in expression level for various CYP450 enzymes (CYP3A4)
Rifampicin is an antimicrobial agent that induces CYP450 expression
Why is induction important?
The mechanisms allows enzymes to change in response to a xenobiotic. It’s a dynamic system that can respond to the environment.
From a drug stand point, it can affect the pharmacokinetics (increased clearance, decreased half life, etc) and pharmacodynamics (decrease response, etc.)
The induction of enzymes is not only a drug interaction phenomenon. Explain.
Induction can be affected by the environment or the patient’s lifestyle (smoking, etc.)
Herbal and nutritional supplements also affect induction
What are different types of drug interactions?
Enzyme inhibitors
Enzyme inducers
Drug A blocks metabolism of drug B
Drug A increases the amount of enzyme for metabolism
Pharmacodynamics: increased/decreased response
Pharmacokinetics: increase/decreased plasma half life
Effects are immediate
Effects are delayed
What are some general examples of inducers?
Ethanol Omeprazole Phenobarbital Rifampin Smoking
What are some general examples of inhibitors?
Cimetidine Erythromycin Grapefruit juice Ketoconazole Quinidine
Explain how cimetidine is an enzyme inhibitor
Cimetidine is an H2 receptor antagonist, used to treat peptic ulcers
It is a potent inhibitor of several different CYP450 enzymes
Drug interactions include warfarin, benzodiazepines, phenytoin, morphine
PK effects: decreased clearance, increased half life
PD effects: increased response, increased duration
How can genetic variability affect the CYP gene family?
It can affect expression levels, enzyme activity, enzyme induction
In general: different phenotypes can affect a patient’s response to drugs. This has implications on the importance of personalized medicine
