ADMET Flashcards
What does ADMET stand for?
Pharmacokinetic Properties Absorption Distribution Metabolism Excretion Toxicity
Why are pharmacokinetic properties important?
Optimize the dosage regimen to account for individual differences who can differ in their therapeutic response and their ability to absorb and eliminate drugs.
What is absorption?
Movement of the drug molecules from the site of administration to the site of measurement (usually bloodstream).
What is distribution?
Reversible transfer of drug to and from the site of measurement.
What is metabolism?
Conversion of one chemical species to another.
What is excretion?
Irreversible loss of a drug.
What is bioavailability?
The fraction of administered drug that reaches the systemic circulation.
What affects absorption?
Routes/sites of administration
Mechanisms of drug absorption
Absorption-based DDIs
Prodrugs
If a drug has an affinity for CYP384 will it have a higher or lower bioavailability?
Lower
What organs have an effect on the First-Pass Effect(aka presytemic elimination)?
Intestines and Liver
Once a drug enters the enterocyte, it may undergo…
Metabolism
Excretion back in to the intestinal lumen
Transport into the portal vein
What are the two types of movement across a plasma membrane?
Passive Transport (Passive diffusion and Facilitated transport) Active Transport
What is the difference between Active and Passive Transport?
Passive - No energy, movement from High to Low
Active - Energy, movement from Low to Hi
Transport of most drugs occurs by facilitated diffusion. T/F
False, transport of most drugs occurs by passive diffusion.
What is Fick’s Law of Diffusion?
Net Drug Flux = Area x Partition coefficient(lipophilicity) x Diffusion coefficient(ionization states) x [Ca-Cp(concentration of drug at absorption site and concentration in plasma)] / Membrane thickness
What are some drugs that are absorbed by passive diffusion?
Acetaminophen, Ibuprofen, Metoprolol, and Diazepam (It looks like they all have phenyl rings and have either an amide or ester/carboxyl group. They also look relatively small (10-15 aliphatic carbons))
How does facilitated transport occur?
A special carrier or transporter molecule is used to move molecules down their concentration gradient without the use of a separate energy source.
What is an example of a drug that uses facilitated transport?
Vitamin B12 across GI membrane
What type of transporters do most drugs use?
Active transporters.
What is Influx?
Transport of substrates from extracellular spaces into cells.
What is Efflux?
Transport of substrates out of cells.
What energy source is Primary Active Transport driven by?
ATP (Ex: ABC transporters)
What energy source is Secondary Active Transport driven by?
Uses the concentration gradient of another substance such as protons, sodium ions, ionic endogenous substances. (Ex: Most SLC carriers)
Concentration gradients that drive secondary active transport are generally created by what?
Primary Active Transporters
Where are ABC transporters located?
On the Apical and basolateral(blood side) membrane of the small intestine and Liver.
On the Apical side of the Kidney.
On the basolateral side of Brain capillaries.
Where are SLC transporters located?
On the apical and basolateral side of the small intestine, kidney, brain capillaries.
On the basolateral side of the kidneys.
What are two families of trasporters?
ABC (ATP-binding cassette) Transporters
SLC (solute carrier) Transporters
SLC transporters are primarily secondary active transporters but includes some….
facilitative transporters
How does primary and secondary active transport work?
Primary active transport by the Na/K ATPase results in a concentration gradient of Na ions.
This drives secondary active transport by the Na/H exchanger.
Transport may be in the same direction, _______, or in opposite directions, _______.
symport
antiport
In active transport, rate of absorption is not directly proportional to the drug concentration in large doses. T/F
True
What is the role of active transport in GIT?
To transport charged/polar molecules
What is the requirements for active transport?
Drug should be structurally similar to the natural substrate of the transporter. Ex: Levodopa is similar(has two extra hydroxyl groups) to Phenylalanine (an amino acid)
What are ABC transporters?
Primary active transporters Efflux transporters Many are located on Apical side (helps in secretion of drugs) Physiologically widespread Extensive range of substrates
What are the ABC transporter families?
MDR (Multidrug Resistance Proteins)
MRP (Multidrug Resistance - Associated Proteins)
BCRP (Breast Cancer Resistance Proteins)
What are the members of the MDR family and the gene names?
MDR1 - ABCB1
What are the members of the MPR family and the gene names?
MRP1 - ABCC1
MRP2 - ABCC2
MRP3 - ABCC3
MRP4 - ABCC4
What are the members of the BCRP family and the gene names?
BCRP1 - ABCG2
What is MDR1 commonly known as?
P-glycoprotein (P-gp)
Where is MDR1 expressed?
In most tissues. Transports in the intestine, liver, kidney, brain, placenta, and tumor cells.
MDR1 transports a small range of molecules. T/F
False, MDR1 transports a large range of molecules.
What are some common features of P-gp substrates?
Generally lipophilic. Which implies that substrates can undergo passive diffusion.
P-gp is an important factor for chemotherapeutic drug resistance due to its…
overexpression in tumor cells.
What contributes to the low bioavailability of several compounds?
Intestinal efflux by P-gp
Why is P-gp important in pregnancy?
P-gp likely protects the fetus from xenobiotics
What are examples of the PgP substrates?
Loperamide (Imodium), digoxin (lanoxin), Fexofenadine HCl (Allegra), Paclitaxel (Taxol).
What are examples of PgP inhibitors?
Verapamil (Calan), Quinidine sulfate (Quinidex).
What are examples of PgP inducers?
Rifampin (Rifadin) and St. John’s Wort
If a PgP substrate and inhibitor are given at the same time, what will happen to the substrates concentration in the plasma?
It will increase.
What are SLC Transporters?
Secondary Active Transporters
Generally facilitate drug influx
Some can facilitate efflux or both influx and efflux
Expressed throughout the body
Transports many xenobiotics and endogenous substances.
What is a xenobiotic?
A foreign chemical substance not normally found in an organisms body.
What are the families of SLC Transporters?
Organic Anion Transporting Polypeptides (OATP) Organic Anion Transporters (OATs) Organic cation transporters (OCTs) Monocarboxylate transporters (MCTs) Peptide Transporters (PEPTs) Nucleoside Transporters (NTs)
What is an example of an MCT and what does it mimic?
Pravastatin mimics mevalonic Acid (Natural substrate)
What endogenous substances does MCT transport?
lactate, pyruvate, mevalonic acid via proton symport
What endogenous substances does PEPT transport?
di and tripeptides via proton symport
Where are PEPT1s located?
Apical membrane of the intestine and lower levels of kidney.
What is PEPT1s function?
Facilitates transport of many therapeutic drugs and prodrugs.
What are the drug substrates for PEPT1?
ACE Inhibitors: Captopril, enalapril
beta-lactams: cephalexin
valacyclovir. (Same drugs as PEPT2)
Where are PEPT2s located?
Apical membrane of the kidney
What are PEPT2s function?
Reabsorb peptides from the urine in renal tubule cells.
What are the drug substrates for PEPT2?
ACE Inhibitors: Captopril, enalapril
beta-lactams: cephalexin
valacyclovir. (Same drugs as PEPT1)
What prodrug does PEPT transport?
Valacyclovir(has valine attached)
Acyclovir, does not have valine, and is thus not a substrate so has a lower bioavailability.
What are the two nucleoside transporter groups?
Concentrative nucleoside transporters (CNTs)
Equlibrative nucleoside transporters (ENTs)
*These two groups work together
Where are CNTs located?
Apical membrane of cells; sodium dependent
Where are ENTs located?
Primarily on basolateral membranes; facilitative
What are nucleoside transporters function?
Uptake of nucleosides (purines and pyrimidines) and their analogs.
What are substrates of nucleoside transporters?
Cytarbine, Gemcitabine, Fludarabine, Ribavirin
all have a sugar and a base
In intestinal transport, which transporters help with drug absorption/bioavailability and which ones decrease drug absorption?
Increase/ Influx - PEPT1, MCT1
Decrease/ Efflux - BCRP, MDR1 (P-gp)
What does a high expression of influx transporters in intestinal transport do?
Allows the use of these transporters as a drug delivery mechanism.
What does a high expression of efflux transporters in intestinal transport do?
It is important in limiting drug bioavailability.
Many of the drug interactions in the intestine involve what transporters?
P-gp or other efflux transporters.
Oral coadministration of rosuvastatin(BCRP substrate) and ritonavir(BCRP inhibitor) will result in an increase or decrease in exposure in humans?
An increase since BCRP is an efflux transporter
If you want to increase drug bioavailability what transporters would you target?
Influx transporters:
PEPT1 (main one for ACE inhibitors, beta lactam antibiotics, valacyclovir)
MCT1
What are some reasons why concurrent use of a drug can affect absorption of another drug?
- have a large surface are upon which the drug can be absorbed
- Specifically from chelates with metal ions and the drugs administered.
- alter gastric pH
- Alter gastrointestinal motility
- Affect transport proteins in GI tract
What are some examples of drugs that cause interactions due to their large surface area and adsorbing?
Activated Charcoal - used in treatment of some types of poisoning.
Complex formation of bile acid sequestering resins colestipol, Cholestryamine with some drugs.
Cholestryamine and Colestipol can interact with what drug and cause what effect?
Loop diuretics causing decreased effect of diuretic.
Cholestryamine can interact with what drug and cause what effect?
Valproic acid causing decreased effects of valproic acid.
Interactions due to substances that form chelate with the metal ions and the drugs administered results in what?
Decreased amount of free drug for absorption.
What are examples of chelation?
Iron with quinolone antibacterials (ciprofloxacin)
Antacids (calcium, magnesium, and aluminum salts) with quinolone antibacterials.
Multivitamin & OTC supplements (zinc, calcium, magnesium, and aluminum salts) with quinolone antibacterials.
Quinolones can chelate polyvalent metal ions (Ca, Mg, Zn, Fe, Al) resulting in…
decreased solubility and reduced drug absorption.
Agents containing polyvalent metals should be administered at least how long before and after quinolones?
4 hours before or 2 hours after.
How does chelation occur?
Between the metal and the 3-carboxylic acid and 4-keto groups.
What interacts with tetracycline antibacterials?
iron, antacids (calcium, magnesium, & aluminum salts)
The acidic functions of the tetracyclinies are capable of forming salts through chelation with…
Fe, Ca, Mg, and Al ions.
Agents containing incompatible metals should be administered at least how long before and after tetracyclines?
1 hour before or 2 hours after
Which drugs can lead to teeth and bones having permanent discoloration?
Tetracyclines. They should not be given to children while they are forming their permanent teeth, ages 6-12 years.
What type of drugs can cause interactions because they alter gastric pH?
Antacids, H2-receptor antagonists, and proton pump inhibitors.
What is an example of a drug that is affected by raising gastric pH?
itraconazole because it has high lipophilicity, it is only water soluble at low pH’s.
What are drugs that can affect gastrointestinal motility?
Loperamide (immodium) will slow down movement.
bisacodyl (Ducolax), a laxative, will increase movement.
Hydrolysis is a type of metabolism because there is a change in the molecule. T/F
True
If Verapamil, a P-gp inhibitor, is coadminsitered with digoxin which is a substrate for P-gp what will happen to digoxin blood levels?
Digoxin blood levels will increase.
If Rifampin, a P-gp inducer, is coadminsitered with digoxin which is a substrate for P-gp what will happen to digoxin blood levels?
Digoxin blood levels will decrease.
What are the advantages and limitations of the sublingual route of administration?
Advantages: Avoidance of first pass effect (60-80% bioavailability)
Rapid absorption
Drug stability
Limitations: Swallowing of the medication.
What are some examples of sublingual route of administration?
Testosterone buccal Mucoadhesive system (Striant)
Sublingual nitroglycerin (Nitrostat)
Fentanyl citrate buccal tablets (Fentora)
What are the advantage and limitations of the rectal route of administration?
Advantages: Avoidance of most of the first-pass effect
Optional route when oral delivery not feasible (unconscious, vomiting)
Best route for treatment of anorectal diseases.
Limitations: Absorption can be incomplete and erratic
Irritation
Limited volumes.
What are some examples of the rectal route of administration?
Pediatric antipyretic products: acetaminophen (Tylenol)
Antinausea suppositories: promethazine HCL (Phenergan)
Anorectal steroid products for irritation: hydrocortisone acetate + pramoxine HCl (Proctofoam-HCl)
What are the advantages of Intravenous route of administration?
Circumvents need for cross-membrane absorption to get drug into circulation.
100% bioavailability
Best route for emergency use.
Can be used with larger volumes and irritants(when diluted)
Can be used for larger peptides & proteins
What are the limitations of intravenous route of administration?
Not suitable for poorly soluble or insoluble agents or oily vehicles.
Most cases require slow administration.
Increased risk of adverse events.
What is the advantages of intramuscular route of administration?
Absorption pattern: 75-100% bioavailability
Prompt (from aqueous solutions), slow (from repository depot preparations).
Can be used with moderate volumes, oily vehicles, some irritants, depot (sustained release) injections.
What is an example of intramuscular route of administration?
Haloperidol decanoate (Haldol D)
What are the limitations of intramuscular route of administration?
May interfere with certain diagnostic tests.
What is an example of a drug that is injected subcutaneously?
Recombinant human insulin (Humulin)
What is intradermal injections used for?
Used for skin testing some allergens.
What are parenteral routes?
IV, Sub-cutaneous, Intradermal, Intrathecal, Intraperitoneal.
What are the advantages of pulmonary/inhalation route of administration?
Best route for treatment of pulmonary diseases.
Absorption: Typically very prompt; 5-100% bioavailability.
What are the limitations of pulmonary/inhalation route of administration?
Limited volumes
Possible irritation
What are some examples of pulmonary/inhalation route of administration?
Inhaled beta-agonists for the treatment of COPD (salmeterol)
Anticholinergics for the treatment of COPD (tiotropium bromide)
Inhaled anesthetics (isoflurane, Forane)
What are the advantages of topical and transdermal drug delivery?
Best absorption with lipid-soluble drugs (steroid creams/ointments) 80-100 % bioavailability.
Best option for the treatment of skin diseases.
Convenience (transdermal patches)
What are the limitations of topical and transdermal drug delivery?
Limited volumes, possible irritation, and variable absorption.
What are some examples of Topical and transdermal Drug Delivery?
Topical steroid formulations (mometasone furoate) Topical antibiotics ( Mupirocin, Bactroban) Topical antifungals (Miconazole, Micantin) Transdermal patches (Scopolamine, transderm-Scop, nitroglycerin, nitrodisc)
