Drug Excretion

Question 1

drug excretion

Answer 1

drugs are eliminated either as unchanged via renal excretion or convered to metabolites in the liver

excrete through urin, bile, or fecal routes

also excretion from lung as gas or breast milk

Question 2

renal excretion of drugs and the three processes involved

Answer 2

90% of 300 drugs in a study were recovered to a significant extend in the urine

three processes include glomerular filtration, tubular secretion, and passive tubular reabsorption

Question 3

glomerular filtration

Answer 3

glomerulus acts as a dialyzing membrane

three layers contribute to the glomerular filtration barrier that serve as size and charge-sensitive filtration systems

about 20% of of the plasma is filtered by glomerulus

drugs bound to proteins such as albumin are not filtered because albumin is too big

Question 4

three layers of the glomerular filtration barrier

Answer 4

capillary endothelium with fenestrae of 60-100 nm (effective pore of 15nm)

negatively charged glomerular basement membrane that is also porous

epithelial podocytes that form interdigitating foot processes with filtration slits of 25-60 nm, effective pore size of <6nm

these layers form a size- and charge-sensitive filter

Question 5

renal drug excretion vs. glomerular filtration

Answer 5

about 80% of filtered ionized drug gets excreted

drug secreted due to filtration alone = GFR x fd (free drug concentration)

net secretion if total renal secreted drug > GFR x fd

net reabsorption if total renal secreted drug < GFR x fd

Question 6

tubular secretion

Answer 6

occurs at the proximal tubules

80% of ionized drug is excreted

some tightly bound drugs, though not filtered will be actrively secreted when it dissosciates

Question 7

transporters in renal secretion

Answer 7

two families of solute carriers on the basolateral side include OATs and OCTs

ABC transporters and SLC transporters on the apical side (urin side) for exporting the drug to the urine

Question 8

drugs carried by organic cation transporters (OCTs)

Answer 8

for weak bases such as procaine, quinidine, and histamine

SLC 22 family transporters OCT1 and 2 mediates facilitated diffusion

on the apical membranes ABC (MDR1) transporters, organic cation/carnitine ttransporters (OCTN1 and 2), and OCT3 transporters

Question 9

drugs carried by organic anion transporters

Answer 9

for weak acids such as penicillin, cephalosporin, and probenecid

OAT1 and OAT3 (SLC22A) are on the basolateral membrane, coupled with alpha-ketoglutarate

MRP2 and MRP4 on the apical side of the membrane, transports OA- into the urine

NPT1/SLC17A1 mediates transport of phosphates usch as PAH, probenicid and penicillin go into the urine

Question 10

passive tubular reabsorption

Answer 10

occurs in the distal tubule

drug transport across is bidirectional, but the net movement is reabsorptive

due to concentrated urine to increase drug concentration of ionized and non-ionized forms

involves passive diffusion of non-ionized drugs

Question 11

probenecid

Answer 11

a drug that competes with the transport system of penicillin, effectively prolonging its time in the body

Question 12

method of enhancing excretion of weak acids

Answer 12

alkalization of uring wiht NaHCO3 intravenous injections

accelerates excretion of weak acids such as barbiturates by increasing the negatively charged form of the drug

Question 13

method of enhancing the excretion of weak bases

Answer 13

acidification of uring with arginine-HCl

increases the positively charged form of the drug

Question 14

factors other than state of drug that affect renal excretion

Answer 14

renal diseases that decrease glomerular filtration decrease drug excretion

drug binding delays excretion if not actively secreted

alteration of drug metabolism influences drug excretion

diuresis increases excretion due to decrease in transit times in tubules

Question 15

transporters and nephrotoxicity

Answer 15

some drugs such as HIV drugs adefovir and cidofovir are toxic to neprhons

Question 16

excretion of drugs >300Da

Answer 16

excreted through the bile

Question 17

drug excretion through the bile

Answer 17

drug passes through the enterohepatic recirculation through sinusoids in the liver

albumin and albumin-bound drugs easily go through the liver fenestrae, which are 150 to 175 nm in diameter

from there, a variety of transporters will transport the drug into the bile

Question 18

ABC5/8

Answer 18

a dimer that exports cholesterol and pytosterols into the bile

defects in either ABC5 or 8 gene causes sisterolemia

xanthomas and premature onset of atherosclerosis may result

Question 19

OATP1B1

Answer 19

pump found in liver cell

if defective, will lead to an increased blood concentration of statins

Question 20

enterohepatic cycle

Answer 20

drugs are metabolized in the liver to form glucuronides

they enter the bile to a large extent

these modified drugs can be cleaved by bacterial beta-glucuronidases in the colon to liberate the drug molecule, which is then reabsorbed

Question 21

effect of enterohepatic recirculation on plasma time concentration of estrone

Answer 21

several stabilizations of the hormones over time

if taken with antibiotics such as minocycline, will inhibit the time that the drug stays in the system

could result in unexpected pregnancies