Pharmacokinetics & Drug Biotransformation Flashcards
Pharmacokinetic Variables (ADME)
-Absorption; How it crosses barriers
-Distribution
-Metabolization
-Excretion
Four methods of Permeation
Different forms of permeation:
- Aqueous Diffusion; If water soluble, water diffuses down it’s concentration gradients typically through aquaporins. Cannot cross this way if the molecule is highly charged or bound to a large protein
- Lipid Diffusion: Lipid soluble drugs such as steroids. The ability to move between aqueous & lipid phases is important for good drug
- Special carriers: Drug binds to the carrier, the carrier will internalize the drug and spit them out into the cell. This is not the target cell. Active transport & Facilitated diffusion
- Endocytosis: Cell surface surrounds the drug, engulfs it, spits it out on the other side
-Exocytosis: Secretion of a substance from the cell. Ex: Neurotransmitters are stored in membrane bound vesicles until ready to use
Volume of Distribution (Vd)
-The space available in the body to contain the drug (theoretical number)
-Relates the amount of drug in the body to the amount of drug in the blood stream
Clearance (Cl)
-Ability of the body to eliminate the drug. Predicts the rate of elimination in relation to drug concentration. Multiple organs play a role here
Concentration (C), Target Concentration (TC), Rate of Elimination (ROE)
-C: The amount of drug given in a volume
-TC: The desired concentration at the effector site
-ROE: Predicted by clearance
Vd & Cl in relation to drugs in the system
-The higher the Vd, the lower the amount of drug in the bloodstream
-The lower the Vd, the higher the amount of drug in the bloodstream
Vd along with clearance will determine the T1/2 of drugs
First Order, Zero Order, Capacity Limited Elimination
1) First order elimination; how most drugs are eliminated from the body. Clearance remains constant, ROE varies
2) Zero order elimination; ROE remains constant. Clearance varies with concentration. Occurs when the body’s ability to eliminate a drug has reached its maximum capacity. (EtOH, ASA, phenytoin)
Capacity limited elimination happens when we have zero order elimination. This can start as first order, but because of the drug amount in the body can become zero-order/ capacity limited
Flow Depend Elimination & The Extraction Ratio
Strictly depends on blood flow through the organ, and whether or not the drug is a high extraction drug.
High extraction means that a large portion of the drug is removed by the organ prior to reaching circulation.
The extraction ratio tells us how much of the drug was removed prior to reaching circulation. Depends on organ health
Extraction Ratios
High : >0.7
Intermediate: 0.3-0.7
Low: <0.3
Half Life ( T1/2)
-The time required for the body to eliminate half of the drug. Half life is dependent upon the extraction ratio, organ health, Vd, and clearance
-In “steady state” dosing (meaning no boluses of the drug have been given), it is generally assumed that it will take 4x half-lives in order to achieve target concentration. Conversely, it should take approximately 4x half lives for the drug to be eliminated from the body
Accumulation
The drug continues to accumulate in the body until dosing stops. Can reach toxic levels of the drug if our dosing intervals are shorter than 4x half-lives
Bioavailability (F)
The fraction of unchanged drug reaching systemic circulation
Seven Routes of Administration & their (F)
- IV 100%
- IM 75 -100%
- Sub-Q 75 -100%
- PO 5 -<100%
- Rectal 30 -<100%
- Inhalation. 5 -<100%
- Transdermal 80- 100%
Peak & Trough
Peak: When a drug is at its highest concentration. Draw levels 5-10mins after administration
Trough: When the drug is at its lowest concentration. Draw levels 30 mins before next dose
Drug Biotransformation
The drug is metabolically converted, either into an inactive metabolite or a metabolite that is more active.
Primarily occurs in the liver
Active Drug & Prodrug
Active Drug: Sufficiently lipid soluble and stable to be given as is. Readily available to reach its intended site of action through a convenient route
Prodrug: An inactive precursor that is absorbed and converted into an active metabolite by a biological process (biotransformation)
First Pass Effect
When an oral drug is absorbed, intact, from the small intestine and transported through the hepatic portal system through the liver, where it undergoes extensive metabolism before reaching systemic circulation
Blood Flow Through The Liver (GI Tract)
GI tract —> absorbed into intestinal capillaries —> reaches the hepatic portal vein —> combines with the splenic vein a series of capillaries (portal system, the hepatic sinusoids)
These capillaries are very leaky. The drug can leak from the capillaries into the hepatocytes where biotransformation will occur. Drug is either put back into the bloodstream or excreted through the bile.
Once back in the bloodstream —> enters the hepatic vein —> to the vena cava —> heart & systemic circulation
Blood Flow Through The Liver (IV Drugs)
Vena Cava–> Heart –> Aorta –> Hepatic Artery–> Hepatic Sinusoids
Phase I Metabolic Reaction
(Oxidation, Reduction, Dehydrogenation, Hydrolysis)
Phase I Reactions:
-Converts a drug into a more polar metabolite.
-Adds or unmasks a functional group (-OH, -NH)
-Usually makes the drug more readily excretable; a lipophilic drug becomes more hydrophilic
Oxidation: Loss of an e-
Reduction: Gain of an e-
Dehydrogenation: Remove an OH group
Hydrolysis: Breaks down water
Oxidation and reduction always happen together
Cytochrome P450
Generic Cyp450 Pathway
Cytochrome P450: A protein with a heme. Function is to introduce an oxygen to xenobiotic compound
Cyp450 Oxidation-Reduction requires P450, P450 Reductase (flavoprotein), NADPH, and molecular oxygen
P450 (Fe3+) combines with RH group (drug)
P450(Fe3+)-RH
–> NADPH donates e- to P450 reductase –> P450 (Fe2+)-RH
–> NADPH donates another e- to P450 reductase, reduces molecular oxygen–> O2-P450(Fe2+)-RH
–> Activated oxygen is transferred to the drug substrate group to form P450(Fe3+)-ROH = making the drug more water soluble
Cytochrome P450 Isoforms (Including wildtype)
CYP3A4- Responsible for metabolization of 50% of all drugs undergoing Phase I
CYP2B6, CYP2D6 also important
CYP3A4 *1 is the “wild type,” meaning, most commonly seen
Phase II Reactions: Conjugation
-Adding molecules to something typically resulting in the compound being more polar, readily excretable, and inactivated
Types of Conjugation:
-Glucuronidation: UDP glucuronic acid carries a glucose-like substance to the drug compound & attaches it.
-Glutathione: Glutathione-S-Transferase attaches glutathione molecule. Important for detoxification
-Acetylation
-Sulfation
-Glycine
-Methylation
-Water conjugation
Hepatic Enzyme Induction
Induction of P450: Increases the presence of P450
DECREASED drug effect if P450 deactivates drug
INCREASED drug effect if P450 activates drug
Ex: Drug 1 given (metabolized by P450)
Drug 2 given (inducer of P450) –> Drug 1 becomes inactivated much more quickly
Prodrug given –> activated by P450–> Drug 3
Drug 2 also given –> can reach toxic levels of drug 3 quickly because Drug 2 is an inducer of P450
Hepatic Enzyme Inhibition
P450 Inhibition: Decrease activity or irreversibly inhibit
Ex:
Drug 1 given (inactivated by p450)
Drug 4 is given (inhibits P450) –> Drug 1 can reach toxic levels
Tylenol Metabolism
95% of APAP will undergo two Phase II reactions. The other 5% undergoes the P450 pathway
- Glucuronidation –> APAP glucuronide–> some APAP+ glucuronide will cross the BBB–> remaining will be transported back into the intestine by ABC transporters–> usually excreted in feces
- Sulfation –> APAP sulfate–> excreted
Accounts for 95% of Tylenol’s metabolism
If traditional pathways are overwhelmed, an alternative pathway has to be activated:
GSH (Glutathione) Conjugation; Little or no hepatotoxicity will occur as long as there is hepatic GSH available for conjugation. If hepatic GSH is being depleted faster than it can be regenerated, reactive, toxic metabolites begin to accumulate. A reactive metabolite (N-acetylbenzoiminoquinone) reacts with cell membranes, proteins, and sugars resulting in hepatotoxicity and death
Additional Factors That Affect Drug Metabolism
-Diet; Charcoal Broiling (Induces CYP1A)
Grapefruit juice (Inhibits Cyp3A)
-Cigarette Smoke
-Age, Sex
-Disease status
-Genetics
6MP & TPMT Mutations
TPMT Mutations mean that they may not be able to metabolize this drug properly. The enzyme is less active. Will need reduced dose or may not be able to take the drug at all
Warfarin & CYP2C9
CYP2C9 isoform means that the patient is either a slow metabolizer or an ultra rapid metabolizer
Herceptin & HER2
If the tumor is overexpressing HER2, the patient is a candidate for Herceptin therapy
Why is pharmacogenomics important in personalized medicine?
We are studying genetic factors and how they affect variation in drug response.
Genetic information is used to guide drug and dosing selection
Role of drug transporters & drug efflux transporters
And factors that affect drug transport
-Drug transporters are located in the endothelial cells of many tissues (intestinal, renal, hepatic) and mediate selective uptake of endogenous compounds and xenobiotics
-Molecular weight, pKa, lipid solubility, and plasma protein
-Drug efflux transporters are membrane proteins that specialize in expelling foreign molecules
Important ABC transporters & their drug affinity
-These transporters bind ATP. ATP binding cassette (ABC)
-ABCB: Broadest substrate specificity; Antineoplastics, HIV protease inhibitors, abx, antidepressants, antiepileptics, opioids
-Drug interactions w/ ABCB: Cyclosporine, quinidine, ritonavir & dig.
When loperamide & quinidine are given together, causes CNS effects
-ABCC: Antineoplastics
-ABCG: Breast cancer resistance protein; antineoplastic, toxins, food-borne carcinogens, folate transport
Drug transporters in different organs & their overall effects
GI, Liver, BBB
GI tract: Transporters are localized in microvilli, transport drugs from the intestine into the bloodstream
Liver: Transporters typically bring drug into the liver.Metabolize xenobiotics and excrete metabolites into bile
BBB: Allows certain drugs to cross into the BBB (highly hydrophobic), but overall most things are going to be pushed back out
Components of the intact BBB
-Functional separation of the circulating blood from the extracellular fluid in the CNS
1. Specific transporters
2. Endothelial cells & tight junctions
3. The cells that surround it; astrocytes and pericytes (podocytes)
