ADMET: Elimination

Objective

List the Routes of Elimination / Excretion (8)

- Kidneys / Urine

- Bile / Feces

- Lungs / Exhalation

- Breast Milk

- Skin / Sweat

- Tears

- Hair

- Saliva

Kidneys / Urine:

- Kidneys are the ________________ excretory organs

- Primary route for __________________ drugs and metabolites

• Kidneys are the primary excretory organs

• Primary route for water-soluble drugs & metabolites

Bile / Feces:

- Primary route for _________________ drugs and metabolites

• Primary route for lipid-soluble (and less water-soluble) drugs & metabolites

Lungs / Exhalation:

- Primary for ____________________

• Primarily for inhaled anesthetics

Breast Milk:

- not a major route of drug / metabolite elimination, but is clinically important for........

passing drugs from mother to a nursing infant

Skin / Sweat:

- not a major route of drug / metabolite elimination, but may be used for...

• monitoring or testing

Tears:

not a major route of drug / metabolite elimination, but may be a concern for....

contact lens wearers

Hair:

not a major route of drug / metabolite elimination, but may be used for....

monitoring or testing

Saliva:

not a major route of drug / metabolite elimination, but may be used for....

monitoring or testing

Objective

Examples of water-soluble drugs released through the kidneys and urine (3)

- vancomycin

- atenolol

- ampicillin

Dosage adjustments of what drugs are required in cases of kidney disease? (3)

- aminoglycoside antibiotics (amikacin, tobramycin)

- cephalosporin antibiotics (fortaz)

- procainamide

- Only _____________ drug is filtered by the kidneys.

- ______________________ fraction is not excreted

- unbound

- plasma protein-bound

The overall rate of drug elimination by the kidneys is a balance that is determined by several factors: (3)

- Drug filtration

- Drug secretion (active transport proteins invovled)

- Drug reabsorption (can be affected by pH changes)

_____________________ are involved in the secretion and reabsorption of drugs and metabolites (in both kidneys & GI tract)

Active transport proteins

(OATPs, POTs, PGPs, MRP2 transporters)

Objective

What can affect the elimination of ionizable drugs and metabolites?

pH changes in urine ("pH trapping")

Objective

what can result due to pH trapping? (3)

- passive elimination of unionized form of drug

- compound becomes ionized once in urine

- it is much more difficult to be passively reabsorbed in ionized form, so it is now "trapped" and eliminated

Objective

List an example of how pH trapping can be used therapeutically

treatment of aspirin overdose with sodium bicarbonate (via alkalinization of urine)

Objective

Examples of lipid-soluble drugs released through bile/feces (3)

- digoxin

- steroids (prednisone)

- hydrophobic anticancer agents

What can biliary/fecal excretion be affected by?

intestinal and biliary diseases

What is involved in the secretion of drugs and metabolites in bile/feces?

Active transport proteins

(OATPs, POTs, PGPs, MDR/MRP)

Objective

_______________________ is possible in bile/feces elimination

Enterohepatic recycling

Objective

What is enterohepatic recycling?

- drug/metabolite is excreted via bile/feces into intestines for elimination

- reabsorption occurs prior to elimination ("recycling")

Objective

List examples of drugs known to undergo enterohepatic recycling? (3)

- atovaquone

- Ezetimibe

- Isotretinoin

Objective

List examples of drugs eliminated through lungs/exhalation

- Isoflurane (99% unchanged via exhalation)

- Sevoflurane (95% eliminated thru exhalaiton)

At least one transport protein, _________, is known to be involved in the active transport of drugs into breast milk

BCRP

Objective

List examples of drugs that are transported into breast milk (2)

- topotecan

- cimetidine

Objective

What medications cause effects when eliminated through tears? (2)

What can this cause?

- Rifampin (causes orange-red color in fluids)

- Azo-based compounds, phenazopyridine (similar effects)

- may cause permanent staining of contact lenses

Objective

The 2 known active transporter families in humans

- Solute carrier (SLC) protein superfamily

- ATP-binding cassette (ABC) superfamily

The 2 kinds of Solute carrier (SLC) proteins

•Organic anion-transporting polypeptides (OATPs)

•Proton-dependent oligopeptide transporters (POTs)

The 3 kinds of ATP-binding cassette (ABC) proteins

•P-glycoprotein (PGP/MDR) efflux pumps

•Multidrug resistance (MRP) efflux pumps

•Breast cancer resistance protein (BCRP)

Drugs known to be PGP substrates: (5)

•Digoxin

•HIV protease inhibitors (indinavir)

•Immunosuppressive agents (tacrolimus)

•Opioids (morphine sulfate)

•Loperamide

T/F: "Normal" dosing does not take PGP-mediated effects into account

FALSE

"Normal” dosing does take PGP-mediated effects into account

Drugs known to be PGP inhibitors: (5)

•Cyclosporine A

•Quinidine

•Calcium channel blockers (verapamil) (diltiazem)

•Azole antifungals (itraconazole)

•Macrolide antibiotics (clarithromycin)

Objective

Interaction of quinidine with digoxin

- PGP inhibition

- quinidine blocks PGP-mediated elimination of digoxin

- leads to higher levels of digoxin in the body and potential toxicity (arrhythmias)

Objective

Interaction of quinidine with digoxin is a.....

PGP inhibition

Drugs known to be PGP inducers: (3)

- Rifampin

- Phenobarbital

- St. John's Wort

Objective

St. John's Wort can _____________ the rate and extent of digoxin elimination

increase

Objective

DDI between St. John's Wort and digoxin is a.....

PGP induction